3-arylcarbonyl- and 3-cycloalkyl-carbonyl-1-aminoalkyl-1H-indoles

ABSTRACT

3-Arylcarbonyl- and 3-cycloalkylcarbonyl-1-aminoalkyl-1H-indoles, useful as analgesic, anti-rheumatic and anti-inflammatory agents, are prepared by reacting a 3-arylcarbonyl- or 3-cycloalkylcarbonylindole with an aminoalkyl halide in the presence of an acid-acceptor; by reacting a 1-aminoalkyl-1H-indole with an arylcarboxylic acid halide or a cycloalkanecarboxylic acid halide in the presence of a Lewis acid; or by reacting a 3-arylcarbonyl- or 3-cycloalkanecarbonyl-1-tosyloxyalkyl- or haloalkyl-1H-indole with an amine.

RELATED APPLICATIONS

This is a division of my prior, copending application Ser. No. 409,913,filed Sept. 20, 1989, which is a division of application Ser. No.25,305, filed Oct. 11, 1988, now U.S. Pat. No. 4,885,295, which is acontinuation of my prior application Ser. No. 928,335, filed Nov. 7,1986, now abandoned, which is a division of my prior application Ser.No. 810,942, filed Dec. 19, 1985, now U.S. Pat. No. 4,634,776, which isa continuation of my prior application Ser. No. 755,239, filed July 15,1985, now U.S. Pat. No. 4,581,354, patented Apr. 8, 1986, which is acontinuation-in-part of my prior application Ser. No. 637,931, filedAug. 6, 1984, now abandoned.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to 3-arylcarbonyl- and3-cycloalkylcarbonyl-1-aminoalkyl-1H-indoles which are useful asanalgesic, anti-rheumatic and anti-inflammatory agents.

(b) Information Disclosure Statement

Deschamps et al. U.S. Pat. No. 3,946,029 discloses compounds having theformula: ##STR1## where, inter alia, A is alkylene; R₂ is one to fourcarbon alkyl; R₃ is a 2-, 3- or 4-pyridyl group; and R₄ and R₅ arejoined together to form, with the nitrogen atom, a piperidino,pyrrolidino or morpholino group. The compounds are said to possessfibrinolytic and anti-inflammatory activities.

Essentially the same disclosure is found in Inion et al., Eur. J. ofMed. Chem., 10 (3), 276-285 (1975). Specifically disclosed in both thesereferences is the species,2-isopropyl-3-(3-pyridylcarbonyl)-1-[2-(4-morpholinyl)ethyl]indole.

Herbst U.S. Pat. No. 3,489,770 generically discloses compounds havingthe formula: ##STR2## where, inter alia, R₁ is "diloweralkylamino,pyrrolidinyl, piperidino and morpholino and R₂ is . . .cyclo(lower)alkanoyl and adamantanylcarbonyl". Although not within theambit of the above-defined genus, the Herbst patent also discloses avariety of species where R₂ is an arylcarbonyl group. Specificallydisclosed, for example, is the species"1-p-(chlorobenzoyl)-3-(2-morpholinoethyl)indole". The compounds aresaid to possess anti-inflammatory, hypotensive, hypoglycemic and CNSactivities.

Tambute, Acad. Sci. Comp. Rend., Ser. C, 278 (20), 1239-1242 (1974)discloses compounds of the formula: ##STR3## where n is 2 or 3. Noutility for the compounds is given.

SUMMARY

In a composition of matter aspect, the invention relates to 2-R₂ -3-R₃-carbonyl-1-aminoalkyl-1H-indoles and their acid-addition salts whichare useful as analgesic, anti-rheumatic and anti-inflammatory agents.

In a second composition of matter aspect, the invention relates to 2-R₂-3-R₃ -carbonylindoles useful as intermediates for the preparation ofsaid 2-R₂ -3-R₃ -carbonyl-1-aminoalkyl-1H-indoles. Certain of the 2-R₂-3-R₃ -carbonyl-indoles are also useful as anti-rheumatic agents.

In a third composition of matter aspect, the invention relates to 2-R₂-1-aminoalkyl-1H-indoles also useful as intermediates for thepreparation of said 2-R₂ -3-R₃ -carbonyl-1-aminoalkyl-1H-indoles.Certain of the 2-R₂ -1-aminoalkyl-1H-indoles are also useful asanalgesics.

In a process aspect, the invention relates to a process for preparing2-R₂ -3-R₃ -carbonyl-1-aminoalkyl-1H-indoles which comprises reacting a2-R₂ -3-R₃ -carbonyl-indole with an aminoalkyl halide in the presence ofan acid-acceptor.

In a second process aspect, the invention relates to a process forpreparing 2-R₂ -3-R₃ -carbonyl-1-aminoalkyl-1H-indoles which comprisesreacting a 2-R₂ -1-aminoalkyl-1H-indole with an arylcarboxylic acidhalide or a cycloalkanecarboxylic acid halide in the presence of a Lewisacid.

In a third process aspect, the invention relates to a process forpreparing said 2-R₂ -3-R₃ -carbonyl-1-aminoalkyl-1H-indoles whichcomprises reacting a 2-R₂ 3-R₃ -carbonyl-1-tosyloxyalkyl- or1-haloalkyl-1H-indole with an amine.

In a method aspect, the invention relates to a method of use of the said2-R₂ -3-R₃ -carbonyl-1-aminoalkyl-1H-indoles for the relief of pain orof rheumatic or inflammatory conditions.

In a second method aspect, the invention relates to a method of use ofthe said 2-R₂ -3-R₃ -carbonylindoles for the relief of rheumaticconditions.

In a third method aspect, the invention relates to a method of use ofthe said 2-R₂ -1-aminoalkyl-1H-indoles for the relief of pain.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

More specifically, the invention relates to 2-R₂ -3-R₃-carbonyl-1-aminoalkyl-1H-indoles, which are useful as analgesic,anti-rheumatic and anti-inflammatory agents, having the formula:##STR4## where:

R₂ is hydrogen, lower-alkyl, chloro, phenyl or benzyl (or phenyl orbenzyl substituted by from one to two substituents selected from halo,lower-alkyl, lower-alkoxy, hydroxy, amino, lower-alkylmercapto,lower-alkylsulfinyl or lower-alkylsulfonyl);

R₃ is cyclohexyl, lower-alkoxycyclohexyl, phenyl (or phenyl substitutedby from one to two substituents selected from halo, lower-alkoxy,hydroxy, benzyloxy, lower-alkyl, nitro, amino, lower-alkylamino,di-lower-alkylamino, lower-alkoxy-lower-alkylamino, lower-alkanoylamino,benzoylamino, trifluoroacetylamino, lower-alkyl-sulfonylamino,carbamylamino, lower-alkylmercapto, lower-alkylsulfinyl,lower-alkylsulfonyl, cyano, formyl or oximinomethylene),methylenedioxyphenyl, 3- or 4-hydroxy-1-piperidinylphenyl,1-piperazinylphenyl, (1H-imidazol-1-yl)phenyl,(1-pyrrolyl)phenyl,aminomethylphenyl, guanidinylmethylphenyl,N-cyanoguanidinylmethylphenyl, styryl, lower-alkyl-substituted-styryl,fluoro-substituted-styryl, 2- or 4-biphenyl, 1- or 2-naphthyl (or 1- or2-naphthyl substituted by from one to two substituents selected fromlower-alkyl, lower-alkoxy, hydroxy, bromo, chloro, fluoro,lower-alkoxycarbonyl, carbamyl, cyano, lower-alkylmercapto,lower-alkylsulfinyl, lower-alkylsulfonyl or trifluoromethyl), thienyl,furyl, benzo[b]furyl, benzo[b]thienyl, quinolyl or(N-lower-alkyl)pyrrolyl;

R₄ is hydrogen or from one to two substituents selected fromlower-alkyl, hydroxy, lower-alkoxy or halo in the 4-, 5-, 6- or 7-positions;

C=Z is C=0 or C=NOH;

Alk is α,ω-lower-alkylene having the formula (CH₂)_(n), where n is aninteger from 2 to 6, or such lower-alkylene substituted on the α- or theω-carbon atom by a lower-alkyl group; and

N=B is azido, amino, N-lower-alkylamino, N,N-di-lower-alkylamino,N-(hydroxy-lower-alkyl)amino, N,N-di-(hydroxy-lower-alkyl)amino,N-lower-alkyl-N-(hydroxy-lower-alkyl)amino,N-(lower-alkoxy-lower-alkyl)amino, N-(halo-n-propyl)amino,4-morpholinyl, 2-lower-alkyl-4-morpholinyl,2,6-di-lower-alkyl-4-morpholinyl, 4-thiomorpholinyl,4-thiomorpholinyl-S-oxide, 4-thiomorpholinyl-S,S-dioxide, 1-piperidinyl,3- or 4-hydroxy-1-piperidinyl, 3- or 4-lower-alkanoyloxy-1-piperidinyl,3- or 4-amino-1-piperidinyl, 3- or4-(N-lower-alkanoylamino)-1-piperidinyl,2-cyclohexylmethyl-1-piperidinyl, 1-pyrrolidinyl,3-hydroxy-1-pyrrolidinyl, 1-azetidinyl, 1-piperazinyl,4-lower-alkyl-1-piperazinyl, 4-lower-alkanoyl-1-piperazinyl,4-carbo-lower-alkoxy-1-piperazinyl, hexahydro-4H-1,4-diazepin-4-yl orthe N=B N-oxides thereof.

Preferred compounds of formula I above are those where:

R₂ is hydrogen or lower-alkyl;

R₃ is phenyl, chlorophenyl, fluorophenyl, dichlorophenyl,difluorophenyl, lower-alkoxyphenyl, di-lower-alkoxyphenyl,hydroxyphenyl, lower-alkylphenyl, aminophenyl, lower-alkylaminophenyl,lower-alkanoylaminophenyl, benzoylaminophenyl,trifluoroacetylaminophenyl, lower-alkylmercaptophenyl,lower-alkylsulfinylphenyl, lower-alkylsulfonylphenyl, cyanophenyl,aminomethylphenyl, styryl, 2- or 4-biphenyl, 1-or 2-naphthyl (or 1- or2-naphthyl substituted by lower-alkyl, lower-alkoxy, hydroxy, bromo,chloro or fluoro), 2-thienyl, 2-, 3-, 4- or 5-benzo[b]furyl, 2-, 3-, 4-or 5-benzo[b]thienyl or 2- or 3-(N-lower-alkyl)pyrrolyl;

R₄ is hydrogen or lower-alkyl, lower-alkoxy, fluoro or chloro in the 4-,5-, 6- or 7-positions;

C=Z is C=0;

Alk is 1,2-ethylene (-CH₂ CH₂ -), 1-lower-alkyl-1, 2-ethylene (CHRCH₂-), 2-lower-alkyl-1,2-ethylene (-CH₂ CHR-), where R is lower-alkyl,1,3-propylene (-CH₂ CH₂ CH₂ -) or 1,4-butylene; and

N=B is 4-morpholinyl, 3- or 4-hydroxy-1-piperidinyl, 1-pyrrolidinyl,3-hydroxy-1-pyrrolidinyl, N-lower-alkylamino, N,N-di-lower-alkylamino,N,N-di-(hydroxy-lower-alkyl)amino, 1-piperazinyl,4-lower-alkyl-1-piperazinyl or 4-lower-alkanoyl-1-piperazinyl.

Particularly preferred compounds of formula I within the ambit of theinvention as defined above are those where:

R₂ is hydrogen or lower-alkyl;

R₃ is phenyl, chlorophenyl, fluorophenyl, difluorophenyl,lower-alkoxyphenyl, lower-alkyl-phenyl, aminophenyl,lower-alkylaminophenyl, lower alkanoylaminophenyl,trifluoroacetylaminophenyl, lower-alkylmercaptophenyl,lower-alkylsulfinylphenyl, aminomethylphenyl, 1- or 2-naphthyl (or 1- or2-naphthyl substituted by lower-alkyl, lower-alkoxy, hydroxy, bromo,chloro or fluoro), 2-thienyl, 2-, 3-, 4- or 5-benzo[b]furyl or 2-, 3-,4- or 5-benzo[b]thienyl;

R₄ is hydrogen, lower alkoxy, fluoro or chloro in the 4-, 5-, 6- or7-positions;

C=Z is C=0;

Alk is 1,2-ethylene, 2-lower-alkyl-1,2-ethylene,1-lower-alkyl-1,2-ethylene, 1,3-propylene or 1,4-butylene; and

N=B is 4-morpholinyl, 3- or 4-hydroxy-1-piperidinyl, 1-pyrrolidinyl,3-hydroxy-1-pyrrolidinyl, N,N-di-lower-alkylamino,N,N-di-(hydroxy-lower-alkyl)amino, 1-piperazinyl or4-lower-alkyl-1-piperazinyl.

Other preferred compounds of formula I within the ambit of the inventionas defined above are those where:

R₂ is hydrogen or lower-alkyl;

R₃ is phenyl, fluorophenyl, chlorophenyl, dichlorophenyl,lower-alkoxyphenyl, di-lower-alkoxyphenyl, hydroxyphenyl,lower-alkanoylaminophenyl, benzoylaminophenyl,lower-alkylsulfonylphenyl, cyanophenyl, styryl, 1-naphthyl,lower-alkoxy-substituted-1- or 2-naphthyl, 3-benzo[b]thienyl or 2- or3-(N-lower-alkyl)pyrrolyl;

R₄ is hydrogen or lower-alkyl, lower-alkoxy, fluoro or chloro in the 4-,5-, 6- or 7-positions;

C=Z is C=0;

Alk is 1,2-ethylene, 1-lower-alkyl-1,2-ethylene,2-lower-alkyl-1,2-ethylene, 1,3-propyllene or 1,4-butylene; and

N=B is 4-morpholinyl or 1-pyrrolidinyl.

Still other preferred compounds of formula I within the ambit of theinvention as defined above are those where:

R₂ is hydrogen, lower-alkyl or phenyl;

R₃ is cyclohexyl, lower-alkoxycyclohexyl, phenyl, fluorophenyl,lower-alkoxyphenyl, lower-alkoxy-fluorophenyl, benzyloxyphenyl,methylenedioxyphenyl, lower-alkylphenyl, di-lower-alkylphenyl,lower-alkylsulfonylaminophenyl, carbamylaminophenyl, cyanophenyl,formylphenyl, oximinomethylenephenyl, (1-pyrrolyl)phenyl,guanidinylmethylphenyl, N-cyanoguanidinylmethylphenyl, 2-naphthyl,2-furyl or 2-benzo[b]thienyl;

R₄ is hydrogen or lower-alkyl, hydroxy or lower-alkoxy in the 4-, 5-, 6-or 7-positions;

C=Z is C=0 or C=NOH;

Alk is 1,2-ethylene or 1-lower-alkyl-1,2-ethylene; and

N=B is 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl or the N-oxidesthereof.

Also considered to be within the ambit of the invention are specieshaving the formulas Ia and Ib: ##STR5## where R₂, R₃, R₄, Alk, Z and N=Bhave the meanings given above.

As used herein, unless specifically defined otherwise, the termslower-alkyl, lower-alkoxy and lower-alkanoyl mean monovalent, aliphaticradicals, including branched chain radicals, of from one to about fourcarbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl,sec.-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy,formyl, acetyl, propionyl, butyryl and isobutyryl.

As used herein, the term cycloalkyl means saturated alicyclic groupshaving from three to seven ring carbon atoms, including cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term halo means fluoro, chloro or bromo.

In one method, the compounds of formula I where C=Z is C=0 are preparedby reacting a 2-R₂ -3-R₃ -carbonyl-1H-indole of formula II with anamino-lower-alky halide in the presence of an acid-acceptor: ##STR6##where R₂, R₃, R₄, Alk and N=B have the meanings given above and Xrepresents halogen. The reaction is preferably carried out in an organicsolvent inert under the conditions of the reaction such asdimethylformamide (hereinafter DMF), dimethylsulfoxide (hereinafterDMSO), a lower-alkanol or acetonitrile. Suitable acid-acceptors are analkali metal carbonate, such as sodium carbonate or potassium carbonate,or an alkali metal hydride, such as sodium hydride, an alkali metalamide, such as sodamide, or an alkali metal hydroxide, such as potassiumhydroxide. Preferred solvents are DMF and DMSO, and preferredacid-acceptors are sodium hydride, potassium carbonate and potassiumhydroxide. The reaction is carried out at a temperature in the rangefrom around 0° C. to the boiling point of the solvent used.

The 2-R₂ -3-R₃ -carbonyl-1H-indoles of formula II are in turn preparedby reacting a 2-R₂ -indole with a lower-alkyl magnesium halide andreacting the resulting Grignard with an appropriate R₃ -carboxylic acidhalide. The reaction is carried out in an organic solvent inert underthe conditions of the reaction, such as dimethyl ether, dioxane ortetrahydrofuran (hereinafter THF), at a temperature in the range from-5° C. to the boiling point of the solvent used.

Certain compounds within the ambit of formula II, namely those offormula II': ##STR7## where R₂ ' is hydrogen, lower-alkyl or phenyl; R₃' is fluorophenyl, difluorophenyl, lower-alkoxyphenyl,di-loweralkoxyphenyl, lower-alkoxy-fluorophenyl, methylenedioxyphenyl,aminophenyl, cyanophenyl, 2- or 4-biphenyl, 1- or 2- naphthyl orlower-alkoxy-substituted-1- or 2-naphthyl; and R₄ ' is hydrogen orfluoro are novel species and comprise a further composition aspect ofthis invention.

In another method, the compounds of formula I where C=Z is C=0 areprepared by reacting a 2-R₂ -1-aminoalkyl-1H-indole of formula III withan appropriate R₃ -carboxylic acid halide (R₃ -CO-X) in the presence ofa Lewis acid, such as aluminum chloride, and in an organic solvent inertunder the conditions of the reaction. Suitable solvents are chlorinatedhydrocarbons such as methylene dichloride (hereinafter MDC) or ethylenedichloride (hereinafter EDC). The reaction is carried out at atemperature from 0° C. to the boiling point of the solvent used. Themethod is illustrated by the reaction: ##STR8## where R₂, R₃, R₄, Alk,N=B and X have the meanings given above.

The intermediate 2-R₂ -1-aminoalkyl-1H-indoles of formula III whereinR₂, R₄, Alk and N=B have the previously given meanings comprise yet afurther composition aspect of the present invention. These compounds areprepared by one of two methods. In one method, a 2-R₂ -indole of formulaIV is reacted with an amino-lower-alkyl halide in the presence of anacid-acceptor, in an organic solvent inert under the conditions of thereaction using the same conditions described above for the preparationof the compounds of formula I by alkylation of the compounds of formulaII.

In a second method, a 2-R₂ -indole of formula IV is reacted with ahalo-lower-alkanamide in the presence of a strong base, and theresulting 2-R₂ -1H-indole-1-alkanamide of formula V is then reduced withlithium aluminum hydride. The reaction of the 2-R₂ -indole of formula IVwith the halo-lower-alkanamide is carried out in an appropriate organicsolvent, such as DMF, at a temperature from -5° C. to about 50° C. Thereduction of the amides of formula V with lithium aluminum hydride iscarried out in an inert organic solvent, such as diethyl ether, THF ordioxane, at a temperature from -5° C. to about 50° C. The two methodsare illustrated by the following reaction sequence: ##STR9## where R₂,R₄, Alk and N=B have the meanings given above, and Alk' islower-alkylene having the formula (CH₂)_(n'), where n' is an integerfrom 1 to 5 or such lower-alkylene group substituted on the ω-carbonatom by a lower-alkyl group.

In another method for preparing the compounds of formula I where C=Z isC=0, a 2-R₂ -3-R₃ -carbonyl-10(2-tosyloxy-lower-alkyl)- or(2-halo-lower-alkyl)-1H-indole of formula VI is reacted with a molarequivalent amount of an amine, H-N=B, in an organic solvent inert underthe conditions of the reaction, such as acetonitrile, a lower-alkanol orDMF. The reaction is preferably carried out by heating a solution of thereactants at the boiling point of the mixture. The method is illustratedby the reaction: ##STR10## where R₂, R₃, R₄ and N=B have the meaningsgiven above, and X' represents a toluenesulfonyl or halo group.

The 2-R₂ -3-R₃ -carbonyl-1-(2-tosyloxy-lower-alkyl)or1-(2-halo-lower-alkyl)-1H-indoles of formula VI, where Alk is1,2-ethylene, are in turn prepared by reaction of a 2-R₂ -3-R₃ -carbonylindole of formula II with a lower-alkyl lithium, for example n-butyllithium, in an inert organic solvent, such as THF, dioxane or diethylether, followed by reaction of the resulting lithium salt with ethyleneoxide. Reaction of the resulting 2-R₂ -3-R₃-carbonyl-1-(2-hydroxyethyl)-1H-indole with toluenesulfonyl chloride inthe presence of an acid-acceptor affords the1-(2-tosyloxyethyl)-1H-indoles, while reaction of the product with aphosphorus trihalide affords the corresponding1-(2-haloethyl)-1H-indoles.

The 2-R₂ -3-R₃ -carbonyl-1-(2-halo-lower-alkyl)-1H-indoles of formulaVI, where Alk has the other possible meanings, are prepared by reactionof a 2-R₂ -3-R₃ -carbonyl indole of formula II with anα,ω-dihalo-lower-alkane in the presence of a strong base, such as sodiumhydride in an inert organic solvent, such as DMF. The reaction generallyoccurs at ambient temperature.

The compounds of formula Ia are prepared by reaction of a2-R₂-3-formyl-1-aminoalkyl-1H-indole with an appropriate methyl R₃ ketoneaccording to the reaction: ##STR11## where R₂, R₃, R₄, Alk and N=B havethe meanings given above. The reaction is carried out in the presence ofa mineral acid and in an organic solvent inert under the conditions ofthe reaction. Preferred solvents are lower alkanols, such as methanol orethanol.

The compounds of formula Ib, where Z is C=0, are prepared by reaction ofa 2-R₂ -3-R₃ -carbonylindole of formula II with an epihalohydrin in thepresence of a strong base, such as an alkali metal hydride, in an inertsolvent, such as DMF or DMSO, and reaction of the resulting 2-R₂ -3-R₃-carbonyl-1-[1-(2,3-epoxy)propyl]-1H-indole with an appropriate amine,H-N=B, according to the reactions: ##STR12## where R₂, R₃, R₄, Alk andN=B have the meanings given above.

Another method for preparing the compounds of formula I where R₄ is5-hydroxy and C=Z is C=O comprises reacting benzoquinone with anappropriate N-(Alk-N=B)-N-(1-R₂ -3-oxo-3-R₃ -propenyl)amine of formulaVII in an inert, water immiscible organic solvent, such as nitromethane.The N-(N=B-alkyl)-N-(1-R₂ -3-oxo-3-R₃ -propenyl)amine in turn isprepared by reaction of a 1,3-diketone, R₂ COCH₂ COR₃, with anappropriate aminoalkylamine, B=N-Alk-NH₂ under dehydrating conditions.The reaction is preferably carried out by heating a solution of thereactants in an inert, water immiscible solvent under a Dean-Stark trap.The method is represented by the reaction sequence: ##STR13##

By further chemical manipulations of various functional groups in thecompounds of formulas I, Ia and Ib prepared by one or more of theabove-described methods, other compounds within the ambit of theinvention can be prepared. For example the compounds where R₃ isaminophenyl are advantageously prepared from the corresponding specieswhere R₃ is nitrophenyl by reduction of the latter.

The reduction can be carried out either catalytically with hydrogen, forexample over a platinum oxide catalyst at ambient temperature and in anappropriate organic solvent, such as a lower-alkanol, ethyl acetate oracetic acid or mixtures thereof, at hydrogen pressures from around 30 to60 p.s.i.g., or alternatively the reduction can be carried outchemically, for example with iron in the presence of hydrochloric acidin an appropriate organic solvent, for example a lower-alkanol. Thereaction is carried out at temperatures from ambient to the boilingpoint of the solvent used for the reaction.

The aminophenyl compounds thus prepared can then be acylated orsulfonylated to prepare compounds where R₃ is lower-alkanoylaminophenyl,benzoylaminophenyl, trifluoroacetylaminophenyl orlower-alkylsulfonylaminophenyl by reaction of an appropriate acidanhydride or acid halide with the corresponding species where R₃ isaminophenyl. It is advantageous, although not essential, to carry outthe reaction in the presence of an acid acceptor, such as an alkalimetal carbonate, for example potassium carbonate, or atri-lower-alkylamine, such as trimethylamine or triethylamine. Thereaction is carried out in an inert organic solvent at a temperature inthe range from -5° C. to around 80° C. Suitable solvents are aceticacid, MDC, EDC or toluene.

Other simple chemical transformations which are entirely conventionaland well known to those skilled in the art of chemistry and which can beused for effecting changes in functional groups attached to the R₃-carbonyl group, (C=0)R₃, involve cleavage of aryl ether functions, forexample with aqueous alkali or a pyridine hydrohalide salt to producethe corresponding phenolic compound (R₃ is hydroxyphenyl); preparationof compounds where R₃ is phenyl substituted by a variety of aminefunctions by reaction of the corresponding halophenyl species with anappropriate amine; catalytic debenzylation of benzyloxy-substitutedspecies to prepare the corresponding phenolic compound (R₃ ishydroxyphenyl); catalytic reduction of a nitrile function to produce thecorresponding aminomethyl-substituted species (R₃ is aminomethylphenyl);saponification of amide groups to produce the corresponding aminocompounds; acylation of hydroxy-substituted species to produce thecorresponding esters; acylation of amino-substituted species to preparethe corresponding amides; oxidation of sulfides to prepare either thecorresponding S-oxides or S,S-dioxides; reductive alkylation ofamino-substituted species to prepare the corresponding mono- ordi-loweralkylamino substituted species; reaction of amino-substitutedspecies with an alkali metal isocyanate to prepare the correspondingcarbamylamino-substituted species (R₃ is carbamylaminophenyl); reactionof an aminomethyl-substituted species with adi-lower-alkylcyanocarbonimidodithioate and reaction of the resultingproduct with ammonia to prepare the correspondingN-cyanoguanidinylmethyl-substituted species (R₃ iscyanoguanidinylmethylphenyl); reduction of a cyano-substituted specieswith sodium hypophosphite to prepare a corresponding formyl-substitutedcompound (R₃ is formylphenyl); reaction of a formylphenyl species or aR₃ -carbonyl species with hydroxylamine to prepare the correspondingoximino methylenephenyl-substituted species (R₃ isoximinomethylenephenyl) or the R₃ -carbonyl oximes (C=Z is C=NOH);reaction of an aminophenyl species with a2,5-di-loweralkoxytetrahydrofuran to prepare a (1-pyrrolyl)phenylsubstituted species (R₃ is 1-pyrrolylphenyl); oxidation of the N=Bfunction, for example by fermentative procedures, to prepare thecorresponding N-oxides; or reaction of a 1-aminoalkyl-1H-indole offormula III where R₂ is hydrogen with hexamethylenephosphoramidefollowed by a lower-alkyl halide to prepare the corresponding compoundsof formula III where R₂ is lower-alkyl.

The compounds of formulas I, Ia, Ib and III in free base form areconverted to the acid-addition salt form by interaction of the base withan acid. In like manner, the free base can be regenerated from theacid-addition salt form in conventional manner, that is by treating thesalts with cold, weak aqueous bases, for example alkali metal carbonatesand alkali metal bicarbonates. The bases thus regenerated can beinteracted with the same or a different acid to give back the same or adifferent acid-addition salt. Thus the novel bases and all of theiracid-addition salts are readily interconvertible.

It will thus be appreciated that formulas I, Ia, Ib and III not onlyrepresent the structural configuration of the bases of formulas I, Ia,Ib and III but are also representative of the structural entities whichare common to all of the compounds of formulas I, Ia, Ib and III,whether in the form of the free base or in the form of the acid-additionsalts of the base. It has been found that, by virtue of these commonstructural entities the bases of formulas I, Ia and Ib, and certain ofthe bases of formula III, and their acid-addition salts have inherentpharmacological activity of a type to be more fully describedhereinbelow. This inherent pharmacological activity can be enjoyed inuseful form for pharmaceutical purposes by employing the free basesthemselves or the acid-addition salts formed from pharmaceuticallyacceptable acids, that is acids whose anions are innocuous to the animalorganism in effective doses of the salts so that beneficial propertiesinherent in the common structural entity represented by the free basesare not vitiated by side effects ascribable to the anions.

In utilizing this pharmacological activity of the salts of theinvention, it is preferred, of course, to use pharmaceuticallyacceptable salts. Although water insolubility, high toxicity or lack ofcrystalline character may make some particular salt species unsuitableor less desirable for use as such in a given pharmaceutical application,the water-insoluble or toxic salts can be converted to the correspondingpharmaceutically acceptable bases by decomposition of the salts withaqueous base as explained above, or alternatively they can be convertedto any desired pharmaceutically acceptable acid-addition salt by doubledecomposition reactions involving the anion, for example by ion-exchangeprocedures.

Moreover, apart from their usefulness in pharmaceutical applications,the salts are useful as characterizing or identifying derivatives of thefree bases or in isolation or purification procedures. Like all of theacid-addition salts, such characterizing or purification saltderivatives can, if desired, be used to regenerate the pharmaceuticallyacceptable free bases by reaction of the salts with aqueous base, oralternatively they can be converted to a pharmaceutically acceptableacid-addition salt by, for example, ion-exhange procedures.

The novel feature of the compounds of the invention, then, resides inthe concept of the bases and cationic forms of the new 2-R₂ -3-R₃-carbonyl-1-aminoalkyl-1H-indoles of formulas I, Ia and Ib and the 2-R₂-1-aminoalkyl-1H-indoles of formula III and not in any particular acidmoiety or acid anion associated with the salt forms of the compounds;rather, the acid moieties or anions which can be associated with thesalt forms are in themselves neither novel nor critical and thereforecan be any acid anion or acid-like substance capable of salt formationwith the bases.

Thus appropriate acid-addition salts are those derived from such diverseacids as formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid,succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid,4-methoxybenzoic acid, phthalic acid, anthranilic acid,1-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid,mandelic acid, tropic acid, crotonic acid, acetylenedicarboxylic acid,sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxylic acid,2-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamicacid, methanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid,diethylphosphonic acid, p-aminophenylarsinic acid, phenylstibnic acid,phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid,hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid,perchloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdicacid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid,barbituric acid, boron trifluoride and the like.

The acid-addition salts are prepared by reacting the free base and theacid in an organic solvent and isolating the salt directly or byconcentration of the solution.

In standard pharmacological test procedures, the compounds of formulasI, Ia and Ib have been found to possess analgesic, anti-rheumatic andanti-inflammatory activities and are thus useful as analgesic,anti-rheumatic and anti-inflammatory agents. Certain of the compounds offormula II have been found to possess anti-rheumatic activity, andcertain of the compounds of formula III have been found to possessanalgesic activity, thus indicating usefulness of those species asanti-rheumatic and analgesic agents, respectively.

The test procedures used to determine the analgesic activities of thecompounds have been described in detail in the prior art and are asfollows: The acetylcholine-induced abdominal constriction test, which isa primary analgesic screening test designed to measure the ability of atest agent to suppress acetylcholine-induced abdominal constriction inmice, described by Collier et al., Brit. J. Pharmacol. Chemotherap. 32,295 (1968); a modification of the anti-bradykinin test, which is also aprimary analgesic screening procedure, described by Berkowitz et al., J.Pharmacol. Exptl. Therap. 177, 500-508 (1971), Blane et al., J. Pharm.Pharmacol. 19, 367-373 (1967), Botha et al., Eur. J. Pharmacol. 6,312-321 (1969) and Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966);and the rat paw flexion test, described by Kuzuna et al., Chem. Pharm.Bull., 23, 1184-1191 (1975), Winter et al., J. Pharm. Exptl. Therap.,211, 678-685 (1979) and Capetola et al., J. Pharm. Exptl. Therap. 214,16-23 (1980).

Anti-rheumatic and anti-inflammatory activities of the compounds of theinvention were determined using the developing adjuvant arthritis assayin rats, the plasma fibronectin assay in arthritic rats and the pleurisymacrophage assay in rats. The developing adjuvant arthritis assay wasused in conjunction with the plasma fibronectin assay as a primaryscreening method in the evaluation of compounds for potential use asdisease modifying anti-rheumatic drugs. The procedure used to inducearthritis in rats is a modification of the methods published by Pearson,J. Chron. Dis. 16, 863-874 (1973) and by Glenn et al., Amer. J. Vet.Res. 1180-1193 (1965). The adjuvant induced arthritis bears many of thetraits of rheumatoid arthritis. It is a chronic, progressive, deformingarthritis of the peripheral joints, with a primary mononuclear cellresponse consisting of bone and joint space invasion by pannus. In orderto detect disease modifying anti-rheumatic drug activity, drug treatmentis started before the disease has become irrevocably established. Sincesuch drugs are not designed to be administered prophylactically, drugtreatment of adjuvant arthritis is initiated at a time when the diseaseis developing but is not yet irreversible. Animals develop significantsystemic arthritic disease which can be measured by swelling of thenon-injected rear paw (NIP) 15 to 20 days following an initial injectionon day 1 of complete Freund's adjuvant into the right hindfoot paw.

The important role played by fibronectin in arthritis has been evidencedby clinical [Scott et al., Ann. Rheum. Dis. 40, 142 (1981)]as well asexperimental [Weissmann, J. Lab. Clin. Med. 100, 322 (1982)]studies.Plasma fibronectin measurements are made using the technique of rocketimmuno-electrophoresis. Fibronectin levels in the arthritic rat aresignificantly higher than in normal animals. Nonsteroidal,anti-inflammatory drugs have no influence on the enhanced fibronectinlevels seen in arthritic rats, while disease modifying anti-rheumaticdrugs cause a significant decrease in plasma fibronectin.

The pleurisy macrophage assay is designed to define anti-arthritic drugswhich inhibit macrophage accumulation in the pleural cavity followinginjection of an inflammatory stimulus. Standard disease modifyingantirheumatic drugs are active in this assay while nonsteroidalanti-inflammatory drugs are not. The activity of species in the pleurisymacrophage model thus indicates disease modifying anti-rheumatic drugactivity. The macrophage is the characteristic cell type in chronicinflammatory responses in the rheumatoid synovium as well as othersites. When activated, macrophages produce a large variety of secretoryproducts, including neutral proteases which play a destructive role inarthritis [Ackerman et al., J. Pharmacol. Exp. Thera. 215, 588 (1980)].The in vivo model of inflammatory cell accumulation in the rat pleuralcavity permits quantitation and differentiation of the accumulatedcells. The cellular components are similar to those seen in the inflamedsynovium. It has been hypothesized that drugs which are effectiveinhibitors of pleurisy macrophage activity may also be effective inslowing or reversing progression of arthritic disease (Ackerman supra),and the procedure used is a modification of the method published byAckerman et al.

The compounds of formulas I, Ia, Ib, II and III of the invention can beprepared for pharmaceutical use by incorporating them in unit dosageform as tablets or capsules for oral or parenteral administration eitheralone or in combination with suitable adjuvants such as calciumcarbonate, starch, lactose, talc, magnesium stearate, gum acacia and thelike. Still further, the compounds can be formulated for oral orparenteral administration either in aqueous solutions of the watersoluble salts or in aqueous alcohol, glycol or oil solutions oroil-water emulsions in the same manner as conventional medicinalsubstances are prepared.

The percentages of active component in such compositions may be variedso that a suitable dosage is obtained. The dosage administered to aparticular patient is variable, depending upon the clinician's judgmentusing as criteria: the route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component and the patient's response thereto. An effectivedosage amount of the active component can thus only be determined by theclinician after a consideration of all criteria and using his bestjudgment on the patient's behalf.

The molecular structures of the compounds of the invention were assignedon the basis of study of their infrared, ultraviolet and NMR spectra.The structures were confirmed by the correspondence between calculatedand found values for elementary analyses for the elements.

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points are uncorrected.

EXEMPLARY DISCLOSURE Preparation of Intermediates

A. The Compounds of Formula II

Preparation 1A

To a solution of 0.05 mole of methyl magnesium bromide in about 45 ml.of anhydrous diethyl ether at 0° C. under a nitrogen atmosphere wasadded, dropwise, a solution containing 6.0 g. (0.04 mole) of2,7-dimethylindole in 30 ml. of anhydrous ether. When addition wascomplete, the reaction mixture was stirred at room temperature for onehour, then cooled in an ice bath and treated dropwise with a solution of8.53 g. (0.05 mole) of 4-methoxybenzoyl chloride in 20 ml. of anhydrousether. The mixture was stirred at room temperature for approximatelytwelve hours, then on a steam bath for two hours and then treated withice water. Excess ammonium chloride was added, and the ether layer wasseparated, dried and evaporated to dryness to give a solid which wascollected by filtration and washed thoroughly with water and ether togive 8.5 g. (76%) of 2,7-dimethyl-3-(4-methoxybenzoyl)indole, m.p.182°-184° C.

Preparations 1B-1AU

Following a procedure similar to that described above in Preparation 1A,substituting for the 2,7-dimethylindole and the 4-methoxybenzoylchloride used therein an appropriate 2-R₂ -R₄ -indole and an appropriatearoylchloride (R₃ CO-Cl), the following species of formula II listed inTable A were prepared. In some instances the products, without furtherpurification, were used directly in the next step of the synthesis ofthe final products of formula I, and no melting points were taken. In afew cases, the weight of the products was not obtained, and socalculation of yields of products in those instances are not possible.Here and elsewhere in the tables included with this specification, themelting point of the product (in ° C.) and the recrystallization solventare given in columns headed "m.p./Solv.", and the yield, in percent, ofproduct is given in columns headed "Yield".

                                      TABLE A                                     __________________________________________________________________________    Prepn.                                                                            R.sub.2                                                                             R.sub.3   R.sub.4                                                                              m.p./Solv. Yield                                   __________________________________________________________________________    1B  CH.sub.3                                                                            4-CH.sub.3 C.sub.6 H.sub.4                                                              --     215-217/DMF-H.sub.2 O                                                                    85                                      1C  CH.sub.3                                                                            2-furyl   --                98                                      1D  CH.sub.3                                                                            4-CH.sub.3 SC.sub.6 H.sub.4                                                             --                                                        1E  CH.sub.3                                                                            4-NO.sub.2 C.sub.6 H.sub.4                                                              --                23                                      1F  CH.sub.3                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                             5-F    199-202/i-PrOH                                     1G  CH.sub.3                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                             7-F    204-205/H.sub.2 O                                                                        42                                      1H  CH.sub.3                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                             7-CH.sub.3 O      68                                      1-I CH.sub.3                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                             5-/7-F(a)         55                                      1J  CH.sub.3                                                                            4-FC.sub.6 H.sub.4                                                                      --     199-201/EtOH                                                                             38                                      1K  CH.sub.3                                                                             ##STR14##                                                                              --     210-213/i-PrOH                                                                           60                                      1L  CH.sub.3                                                                            3-benzo[b]thienyl                                                                       --     181-183    64                                      1M  CH.sub.3                                                                            2-benzo[b]furyl                                                                         --     220-220/i-PrOH                                                                           75                                      1N  CH.sub.3                                                                            2-CH.sub.3 OC.sub.6 H.sub.4                                                             --     203-206/i-PrOH                                                                           75                                      1-O CH.sub.3                                                                            3-F-4-CH.sub.3 OC.sub.6 H.sub.3                                                         --     160-165/EtOH                                                                             39                                      1P  CH.sub.3                                                                            2-naphthyl                                                                              --     208-213/i-PrOH                                                                           57                                      1Q  H     4-CH.sub.3 OC.sub.6 H.sub.4                                                             5-CH.sub.3                                                                           189-192/EtOH                                                                             42                                      1R  CH.sub.3                                                                            3-FC.sub.6 H.sub.4                                                                      --                64                                      1S  CH.sub.3                                                                            2-FC.sub.6 H.sub.4                                                                      --     216-218/i-PrOH                                                                           44                                      1T  CH.sub.3                                                                            4-CNC.sub.6 H.sub.4                                                                     --     211-213/EtOAc                                                                            7                                       1U  CH.sub.3                                                                            C.sub.6 H.sub.5                                                                         4-CH.sub.3                                                                           176-179/EtOAc                                                                            65                                      1V  CH.sub.3                                                                            4-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                       --     199-201/EtOAc                                                                            70                                      1W  CH.sub.3                                                                            3-NO.sub.2 C.sub.6 H.sub.4                                                              --     218-221/DMF-H.sub.2 O                                                                    20                                      1X  CH.sub.3                                                                            4-CH.sub.3 C.sub.6 H.sub.4                                                              --     207-209/EtOH                                                                             60                                      1Y  CH.sub.3                                                                            3-CH.sub.3 OC.sub.6 H.sub.4                                                             --     163-164/EtOAc                                                                            63                                      1Z  H     4-CH.sub.3 OC.sub.6 H.sub.4                                                             --                80(b)                                   1AA C.sub.6 H.sub.5                                                                     4-CH.sub.3 OC.sub.6 H.sub.4                                                             --                25                                      1AB H     C.sub.6 H.sub.5                                                                         5-CH.sub.3 O      46                                      1AC CH.sub.3                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                             6-CH.sub.3 O      53                                      1AD CH.sub.3                                                                            4-NO.sub.2 C.sub.6 H.sub. 4                                                             6-CH.sub.3 O      73                                      1AE CH.sub.3                                                                            C.sub.6 H.sub.5                                                                         --     185-186/MeOH                                                                             64                                      1AF H     C.sub.6 H.sub.5                                                                         --     241-242/MeOH                                                                             38                                      1AG CH.sub.3                                                                            4-ClC.sub.6 H.sub.4                                                                     --     183-185/MeOH                                                                             34                                      1AH CH.sub.3                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                             6-Cl              58                                      1AI CH.sub.3                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                             6-C.sub.6 H.sub.5 CH.sub.2 O                                                                    51                                      1AJ CH.sub.3                                                                             ##STR15##                                                                              --     239.5-240/CH.sub.3 CN                                                                    98                                      1AK CH.sub.3                                                                            2-C.sub.6 H.sub.5 C.sub.6 H.sub.4                                                       --     238-240/MeOH                                                                             39                                      1AL CH.sub.3                                                                            4-C.sub.6 H.sub.5 C.sub.6 H.sub.4                                                       --     225-228    56                                      1AM CH.sub.3                                                                            1-naphthyl                                                                              --     223-224/i-PrOH                                                                           69                                      1AN CH.sub.3                                                                            2,3-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                  --     185-187    87                                      1AO CH.sub.3                                                                            3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                  --     182-184    85                                      1AP CH(CH.sub.3).sub.2                                                                  4-CH.sub.3 OC.sub.6 H.sub.4                                                             --     176-178/EtOAc-ether                                                                      44                                      1AQ CH(CH.sub.3).sub.2                                                                  4-CH.sub.3 OC.sub.6 H.sub.4                                                             5-F    173-175    11                                      1AR CH.sub.3                                                                            2-FC.sub.6 H.sub.4                                                                      5-F    247-249/i-PrOH                                                                           10                                      1AS CH.sub.3                                                                            4-CH.sub.3 O-l-naphthyl                                                                 --     286-289/i-PrOH                                                                           24                                      1AT CH.sub.3                                                                            4-C.sub.6 H.sub.5 C.sub.6 H.sub.4                                                       5-F    234-235.5/EtOH                                                                           36                                      1AU CH.sub.3                                                                            4-CH.sub.3 OC.sub.6 H.sub.4                                                             --     200-203    97                                      __________________________________________________________________________     (a)Product consisted of a mixture of the 5fluoro and the 7fluoro isomers.     (b)Two molar equivalents of the Grignard reagent used, thus resulting in      acylation at both the 1 and 3 positions of indole derivative. The desired     product was obtained by heating a mixture of the crude product in methano     and sodium hydroxide.                                                    

Preparation 1AV

A mixture of 50 g. (0.03 mole) of phenylmercaptoacetone and 76.8 g. (0.3mole) of 3-benzyloxyphenylhydrazine in 750 ml. of ethanol was heated ona steam bath for six hours and then stirred at room temperature forabout twelve hours. The solid which separated was collected, washed withwater and the filtrate set aside. The solid was dissolved in methylenedichloride, the organic solution was washed with water, then with dilutehydrochloric acid, dried over magnesium sulfate, filtered and taken todryness to yield a first crop of crude product which was stirred withether for about forty-eight hours and then filtered and dried to give 56g. of product. The original filtrate, previously set aside, was mixedwith methylene dichloride, and the organic layer was washed with water,then with dilute hydrochloric acid, dried over magnesium sulfate,filtered and concentrated to dryness to give 40 g. of additional productwhich was recrystallized from diethyl ether/methylene dichloride to give29.7 g. of product (combined yield 71.7 g., 69%) of2-methyl-3-phenylmercapto-6-benzyloxyindole, m.p. 146°-148° C.

A mixture of 25 g. (0.072 mole) of the latter with 50 teaspoons of aRaney nickel/ethanol suspension in 1 liter of ethanol was heated underreflux for three hours, stirred at ambient temperature for about twelvehours, then refluxed for an additional three hours and the catalystremoved by filtration. The filtrate was taken to dryness in vacuo togive an oil which was passed through a pad of Florisil and eluted withethyl acetate. Evaporation of the solution to dryness afforded 5.2 g.(26%) of 6-hydroxy-2-methylindole.

A mixture of 5 g. (0.034 mole) of the latter, 5.9 ml (0.051 mole) ofbenzyl chloride and 13.8 g. (0.1 mole) of potassium carbonate in 200 mlof DMF was stirred at room temperature for two hours, then heated on asteam bath for two hours and the mixture poured into ice/water. Thesolid which separated was collected, dissolved in ethyl acetate, and theorganic solution was washed with water, then with brine, dried overmagnesium sulfate, filtered and taken to dryness to give 2.5 g. of6-benzyloxy-2-methylindole, m.p. 90°-93° C., used as the startingmaterial for the preparation of the compound of Preparation 1AI in Table1 above.

Preparation 2

To a solution of 20 g. (0.071 mole) of2-methyl-3-(4-methylmercaptobenzoyl)indole (Preparation 1D) in 400 ml.of chloroform was added, dropwise with stirring, a solution of 16.7g.(0.081 mole) of 3-chloroperbenzoic acid (80%) in 170 ml. of chloroformwhile cooling the mixture in an ice/methanol bath. When addition wascomplete, the solution was stirred at room temperature for approximatelytwelve hours and then washed three times with saturated sodiumbicarbonate solution and dried over magnesium sulfate. The mixture wasfiltered, the filtrate was concentrated to near dryness, and the solidwhich separated was collected and recrystallized from ethyl acetate togive 14.5 g. (69%) of 2-methyl-3-(4-methylsulfinylbenzoyl)indole.

Preparation 3

2-Methyl-3-(4-nitrobenzoyl)indole (Preparation 1E) (11.2 g., 0.04 mole)dissolved in a solution of 100 ml. of glacial acetic acid and 200 ml. ofethyl acetate was reduced with hydrogen over 0.6 g. of platinum oxidecatalyst in a Parr shaker, and when reduction was complete, in about twoand a half hours, the catalyst was removed by filtration and the solventtaken off in vacuo to leave 11.4 g. of crude product, which wasrecrystallized from ethanol to give 4.5 g. (45%) of2-methyl-3-(4-aminobenzoyl)indole, m.p. 220°-223° C.

B. The Compounds of Formula III

(a) By Alkylation of the Compounds of Formula IV

Preparation 4A

To a stirred suspension of 229.5 g. (1.22 moles) ofN-(2-chloroethyl)morpholine hydrochloride in 300 ml. of DMSO at ambienttemperature was added 200 g. (3.03 moles) of 85% potassium hydroxidepellets, and the suspension was stirred for five minutes and thentreated dropwise at ambient temperature with a solution of 133.7 g. (1.0mole) of 2-methylindole in 140 ml. of DMSO. The temperature of thereaction mixture gradually rose during the addition of the2-methylindole as well as on stirring after addition was complete. Whenthe temperature reached 78° C., the mixture was cooled in a water bathuntil the temperature subsided to 75° C., and the mixture was stirredfor a total of three and a half hours while the temperature subsided toambient. The mixture was then diluted with 1 liter of water andextracted with toluene. The extracts were washed with water, dried overmagnesium sulfate and taken to dryness in vacuo, and the residual darkoil was crystallized from heptane to give 224 g. (92%) of2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p. 63°-65° C.

Preparation 4B

Following a procedure similar to that described above in Preparation 4A,20.0g. (0.134 mole) of 5-fluoro-2-methylindole were reacted with 24.1 g.(0.147 mole) of 4-(3-chloropropyl)morpholine in 46 ml. of dry DMF in thepresence of 8.0 g. (0.201 mole) of a 60% mineral oil dispersion ofsodium hydride. The product was isolated in the form of its maleate saltto give 30.0 g. (81%) of 5-fluoro-2-methyl-1-[3-(4-morpholinyl)propyl]-1H-indole maleate, m.p. 165°-167° C.

Preparation 4C

Following a procedure similar to that described in Preparation 4A, 50 g.(0.43 mole) of indole were reacted with 159 g. (0.85 mole) of4-(2-chloroethyl)morpholine in 850 ml. of dry DMF in the presence of 209g. (0.50 mole) of a 60% mineral oil dispersion of sodium hydride. Theproduct was isolated in the form of the free base to give 45.6 g. (46%)of 1-[2-(4-morpholinyl)ethyl]-1H-indole.

Preparation 4D

To a stirred suspension of 322 g. (0.81 mole) of a 60% mineral oildispersion of sodium hydride in 250 ml. of dry DMF was added dropwise asolution of 100 g. (0.67 mole) of 5-fluoro-2-methylindole in 300 ml. ofdry DMF. The mixture was stirred at ambient temperature for thirtyminutes and then treated dropwise with cooling with a solution of 121.5g. (0.67 mole) of ethyl α-bromopropionate. Workup of the reactionmixture, after quenching with water and extraction of the product withethyl acetate, afforded ethyl α-(5-fluoro-2-methyl-1-indolyl)propionate.

The latter was reduced with 525 ml. of a 1M solution of diisobutylaluminum in 1150 ml. of toluene to give 130 g. (94%) of5-fluoro-2-methyl-1-(1-methyl-2-hydroxyethyl)-1H-indole.

The latter, on reaction with 144 g. (0.76 mole) of p-toluenesulfonylchloride in 350 ml. of pyridine using the procedure described inPreparation 7A afforded 65 g. (20%) of5-fluoro-2-methyl-1-[1-methyl-2-(p-toluenesulfonyloxy)ethyl]-1H-indole,m.p. 136°-140° C.

(b) Via the Amides of Formula V

Preparation 5A

Following a procedure similar to that described in Preparation 4 above,32.8 g. (0.25 mole) of 2-methylindole in 160 ml. of dry DMF was reactedwith 13.4 g. (0.28 mole) of a 50% mineral oil dispersion of sodiumhydride in 200 ml. of dry DMF, and the resulting sodium salt was thenreacted with 62 g. (0.28 mole) of 4-(α-bromopropionyl)morpholine in 160ml. of DMF to give 55.3 g. (59%) of4-[α-(2-methyl-1H-indol-1-yl)propionyl]morpholine.

The latter (130 g., 0.48 mole), dissolved in 900 ml. of THF, was addedto 80 ml. (0.80 mole) of a solution of boron methyl sulfide complex inTHF under nitrogen while cooling in an ice bath. When addition wascomplete, the mixture was stirred for eighteen hours at roomtemperature, heated under reflux for four hours, quenched by addition ofabout 1 liter of methanol, boiled for about fifteen minutes,concentrated essentially to dryness and then diluted with aqueous 6Nhydrochloric acid. The mixture was extracted with methylene dichloride,and the raffinate was basified with 35% sodium hydroxide and extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried and concentrated to dryness to give 42.6 g. (34%) of2-methyl-1-[1-methyl-2-4-morpholinyl)ethyl]-1H-indole as an oil. Aportion of the latter was reacted with methanesulfonic acid to give themonomethanesulfonate as the 4:1 hydrate, m.p. 154°-157° C.

Preparation 5B

Following a procedure similar to that described in Preparation 5A above,29.29 g. (0.25 mole) of indole in 200 ml. of dry DMF was reacted with13.4 g. (0.28 mole) of a 50% mineral oil dispersion of sodium hydride in200 ml. of dry DMF and the resulting sodium salt reacted with 62.0 g.(0.28 mole) of 4-(α-bromopropionyl)morpholine in 200 ml. of dry DMF andthe product recrystallized from isopropanol to give 13.7 g. (21%) of4-[α-(1H-indol-1-yl)propionyl]morpholine, m.p. 92°-94° C. The latter (20g., 0.078 mole) in 300 ml. of diethyl ether was reduced with 3.12 g.(0.078) mole of lithium aluminum hydride in 100 ml. of diethyl ether togive 17 g. (90%) of 1-[1-methyl-2-(4-morpholinyl)ethyl]-1H-indole, m.p.35°-37° C.

Preparation 5C

Following a procedure similar to that described in Preparation 5B, 83 g.(0.63 mole) of 2-methylindole was reacted with 30 g. (0.75 mole) of a60% mineral oil dispersion of sodium hydride, and the resulting sodiumsalt was reacted with a molar equivalent amount of4-(α-bromobutyryl)morpholine in 100 ml. of DMF. The crude product thusobtained was reduced with 25 g. (0.66 mole) of lithium aluminum hydridein 500 ml. of THF. The product was isolated in the form of thehydrochloride to give 53.4 g. (27%) of2-methyl-1-[1-ethyl-2-(4-morpholinyl)ethyl]-1H-indole hydrochloride,m.p. 159°-162° C. (from ethyl acetateether).

Preparation 6

To a solution of 23 g. (0.1 mole) of1-[2-(4-morpholinyl)ethyl]-1H-indole (Preparation 4C) in 120 ml. of THFwas added 60 ml. of 2.1M butyl lithium in hexane while maintaining thetemperature at 0° C. The mixture was allowed to warm up to roomtemperature and was then treated with 18 ml. of hexamethylphosphoramidefollowed by 10 ml. of ethyl iodide while maintaining the temperature at0° C. The mixture was then quenched with ice, extracted with ether, andthe combined organic extracts were washed first with water, then withbrine, dried over magnesium sulfate, taken to dryness andchromatographed on silica gel, eluting with 40:50 ethyl acetate:hexane.Four fractions were obtained which, on evaporation to dryness, afforded4.0 g. of a yellow oil from the first fraction and 9.6 g., 3.6 g. and4.2 g. of solid material in the next three fractions. These fractionswere recrystallized from hexane to give 8.3 g. (32%) of2-ethyl-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p. 59°-60.5° C.

C. The Compounds of Formula VI

Preparation 7A

To a suspension of 50 g. (0.19 mole) of2-methyl-3-(4-methoxybenzoyl)indole (Preparation 1AU) in 400 ml. of THFwas added, over a one and a half hour period, 74.25 ml. (0.19 mole) of a2.6M solution of n-butyl lithium in hexane. The reaction mixture wasstirred for one hour at 0° C., at room temperature for forty-fiveminutes, recooled to 0° C. and treated dropwise, over a thirty minuteperiod, with a solution of 93.7 ml. (0.19 mole) of a 2.06 M solution ofethylene oxide in THF. The reaction mixture was gradually allowed towarm to room temperature and then treated with 200 ml. of a saturatedammonium chloride solution. The solvent was removed in vacuo, theresidual solid was filtered, washed with water and extracted withboiling ether, and the ether extracts were taken to dryness to give 23g. (39%) of 2-methyl-3-(4-methoxybenzoyl)-1-(2-hydroxyethyl)-1H-indole,m.p. 75°-78° C.

A solution of 10 g. (0.032 mole) of the latter and 6.48 g. (0.034 mole)of p-toluenesulfonyl chloride in 100 ml. of pyridine was stirred at roomtemperature for about twelve hours and the reaction mixture diluted withethyl acetate and washed with water. The organic layer was separated,dried over magnesium sulfate, filtered and concentrated to dryness togive a brown gum. The latter was dissolved in methylene dichloride andthe solution chromatographed on a short column of Florisil to give 7.8g. (52%) of2-methyl-3-(4-methoxybenzoyl)-1-(2-p-toluenesulfonyloxyethyl)-1H-indole,m.p. 62°-65° C.

Preparation 7B

Following a procedure similar to that described in Preparation 7A above,9.75 g. (0.0375 mole) of 2-methyl-3-(4-cyanobenzoyl)indole (Preparation1T) in 125 ml. of THF was treated with 16.65 ml. (0.04 mole) of a 2.4Msolution of n-butyl lithium in hexane followed by 11.4 ml. of a 3.5Msolution of ethylene oxide in THF to give2-methyl-3-(4-cyanobenzoyl)-1-(2-hydroxyethyl)-1H-indole. Reaction of30.4 g. (0.1 mole) of the latter with 21.0 g. (0.11 mole) ofp-toluenesulfonyl chloride in 50 ml. of methylene dichloride in thepresence of 50 ml. of 35% sodium hydroxide and 0.91 g. (0.004 mole) ofbenzyl trimethylammonium chloride afforded 38.3 g. (84%) of2-methyl-3-(4-cyanobenzoyl)-1-(2-p-toluenesulfonyloxyethyl)-1H-indole,m.p. 165°-167° C.

Preparation 7C

Following a procedure similar to that described in Preparation 7A above,20 g. (0.1 mole) of 2-methyl-3-(4-ethylbenzoyl)indole (Preparation 1V)in 200 ml. of THF was treated with 51 ml. (0.11 mole) of a 2.15 Msolution of n-butyl lithium in hexane followed by 6.16 g. (0.13 mole) ofethylene oxide to give 18 g. (73%) of2-methyl-3-(4-ethylbenzoyl)-1-(2-hydroxyethyl)-1H-indole. Reaction ofthe latter (0.058 mole) with 14.32 g. (0.075 mole) of p-toluenesulfonylchloride in 400 ml. of methylene dichloride in the presence of 50 ml. of35% sodium hydroxide and 1.6 g. (0.0076 mole) of benzyltrimethylammonium chloride afforded 27 g. (95%) of2-methyl-3-(4-ethylbenzoyl)-1-(2-p-toluenesulfonyloxyethyl)-1H-indole asa red oil.

Preparation 7D A solution of 5.0 g. (0.068 mole) of2-methyl-5fluoro-3-(4-methoxybenzoyl)indole (Preparation 1F) in 100 ml.of dry DMF was cooled in an ice bath at 0° C and then treated with 18.17g. (0.09 mole) of 1,3-dibromopropane. The solution was stirred for a fewminutes at 0° C, then treated portionwise with 1.08 g. (0.027 mole) of a60% mineral oil dispersion of sodium hydride, stirred for about fifteenminutes in an ice bath, then for an additional twelve hours at ambienttemperature, treated with a small amount of water and taken to drynessin vacuo. The residue was partitioned between water and methylenedichloride, the organic layer was separated, washed first with water,then with brine and then dried and taken to dryness. Crystallization ofthe residue from ethanol afforded 4 g. (55%) of1-(3-bromopropyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1H-indole, m.p.133°-135° C.

Preparation 7E

Following a procedure similar to that described in Preparation 7D above,60 g. (0.23 mole) of 2-methyl-3-(4-methoxybenzoyl)indole (Preparation1AU) was reacted with 244.1 g. (1.13 mole) of 1,4-dibromobutane in 200ml. of DMF in the presence of 13.8 g. (0.34 mole) of a 60% mineral oildispersion of sodium hydride, and the product recrystallized from ethylacetate/hexane to give 5.0 g. of1-(4-bromobutyl)-2-methyl-3-(4-methoxybenzoyl)-1H-indole, m.p. 83°-86°C.

Preparation 7F

Following a procedure similar to that described in Preparation 7D above,35 g. (0.122 mole) of 2-methyl-3-(1naphthylcarbonyl)indole (Preparation1AM) was reacted with 124 g. (0.614 mole) of 1,3-dibromopropane in 700ml of DMF in the presence of 7.5 g. (0.188 mole) of a 60% mineral oildispersion of sodium hydride, and the product purified by chromatographyon Kieselgel 60 in 50% ethyl acetate/hexane. There was thus obtained18.38 g. (37%) of1-(3-bromopropyl)-2-methyl-3-(1-naphthylcarbonyl)-1H-indole, m.p.115°-116° C.

Preparation 7G

Following a procedure similar to that described in Preparation 7D above,73.86 g. (0.3 mole) of 2-methyl-3-(4-methoxybenzoyl)indole (Preparation1AU) was reacted with 302.33 g. (1.5 moles) of 1,3-dibromopropane in 250ml. of DMF in the presence of 17.97 g. (0.45 mole) of a 60% mineral oildispersion of sodium hydride. There was thus obtained1-(3-bromopropyl)-2-methyl-3-(4-methoxybenzoyl)-1H-indole.

Preparation 7H

Following a procedure similar to that described in Preparation 7D above,15.0 g. (0.053 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)indole(Preparation 1F) was reacted with 9.18 g. (0.058 mole) of1-bromo-3-chloropropane in 232 ml. of DMF in the presence of 3.2 g.(0.0795 mole) of a 60% mineral oil dispersion of sodium hydride. Therewas thus obtained 15.3 g. (80%) of1-(3-chloropropyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1H-indole.

Preparation 7I

Following a procedure similar to that described in Preparation 7A above,24.8 g. (0.087 mole) of 2-methyl-3(1-naphthylcarbonyl)indole(Preparation lAM) in 300 ml. of THF was treated with 35 ml. (0.09 mole)of a 2.6M solution of n-butyl lithium in hexane followed by 56 ml. of a2.6M solution of ethylene oxide in THF to give 21.3 g. (74%) of2-methyl-3-(1-naphthylcarbonyl)-1-(2-hydroxyethyl)-1H-indole. Reactionof the latter (0.065 mole) with 18.5 g. (0.097 mole) ofp-toluenesulfonyl chloride in 400 ml. of methylene dichloride in thepresence of 340 ml. of 35% sodium hydroxide and 0.6 g. (0.0026) mole ofbenzyl trimethylammonium chloride afforded 20.1 g. (64%) of2-methyl-3-(1-naphthylcarbonyl)-1-(2-p-toluenesulfonyloxyethyl)-1H-indoleas a viscous oil.

Preparation 8

A solution of 42 g. (0.116 mole) of5-fluoro-2-methyl-1-[1-methyl-2-(p-toluenesulfonyloxy)ethyl]-1H-indole(Preparation 4D) and 50 ml. of morpholine in 400 ml. of DMF was heatedon a steam bath for seventy-two hours, poured into water and the mixtureextracted with ethyl acetate. The combined organic extracts were driedand taken to dryness to give 20 g. of crude product which was purifiedby HPLC, eluting the product with 2:1 hexane:ethyl acetate. There wasthus obtained 10.4 g. (32%) of5-fluoro-2-methyl-1-[1-methyl-2-(4-morpholinyl)ethyl]-1H-indole as thefirst, third and fourth through the seventh fractions.

The second fraction, on conversion to the hydrochloride salt andrecrystallization from methanol-ether, afforded 1.0 g. of5-fluoro-2-methyl-1-[1-methyl-2-(dimethylamino)ethyl]-1H-indolehydrochloride, m.p. 208.5°-211.5° C., produced by amination of thetosylate by the DMF used as a solvent.

It is contemplated that, by replacing the morpholine in theabove-described procedure with dimethylamine, the dimethylamino speciescan be obtained as the major product.

Preparation 9A

Following a procedure similar to that described in Preparation 5A above,24.0 g. (0.071 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)indole(Preparation 1F) in 200 ml. of dry DMF was reacted with 35.2 g. (0.35mole) of epichlorohydrin in the presence of 3.1 g. (0.078 mole) of a 60%mineral oil dispersion of sodium hydride in 100 ml. of DMF. The productwas recrystallized from ethyl acetatehexane to give 10.6 g. (44%) of5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[1-(2,3-epoxy)propyl]-1H-indole as a yellow solid.

Preparation 9B

Following a procedure similar to that described in Preparation 9A above,100 g. (0.377 mole) of 2-methyl-3-(4-methoxybenzoyl)indole (Preparation1AU) in 1500 ml. of DMF was reacted with 174.6 g. (1.89 moles) ofepichlorohydrin in the presence of 19.92 g. (0.42 mole) of a 50% mineraloil dispersion of sodium hydride in 500 ml. of DMF. There was thusobtained2-methyl-3-(4-methoxybenzoyl)-1-[1-(2,3-epoxy)propyl]-1H-indole.

Preparation 9C

Following a procedure similar to that described in Preparation 9A above,28.7 g. (0.1 mole) of 2-methyl-3-(1-naphthylcarbonyl)indole (Preparation1AM) in 165 ml. of DMSO was reacted with 27.39 g. (0.2 mole) ofepibromohydrin in the presence of 6.6 g. (0.1 mole) of powderedpotassium hydroxide and the product purified by chromatography on silicagel, eluting with ethyl acetate-hexane. There was thus obtained 32.3 g.(95%) of 2-methyl-3-(1-naphthyl-carbonyl)-1-[1-(2,3-epoxy)propyl]-1H-indole.

PREPARATION OF THE FINAL PRODUCTS OF FORMULA I A. From the Compounds ofFormula II

Example 1A

Following a procedure similar to that described in Preparation 4 above,25 g. (0.10 mole) of 3-(4-methoxybenzoyl)indole (Preparation 1Z) in 100ml. of DMF was reacted with 5.76 g. (0.12 mole) of a 50% dispersion ofsodium hydride in mineral oil in 120 ml. of DMF, and the resultingsodium salt was reacted with 0.14 mole of 4-(2-chloroethyl)morpholine(freed from 26.06 g. of the corresponding hydrochloride) in 120 ml. ofDMF to give 42 g. of the crude product as an oil which, on triturationwith ethyl acetate/diethyl ether/hexane, gave a yellow crystalline solidwhich was converted to the methanesulfonate salt to afford 9.5 g. (20%)of 3-4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indolemethanesulfonate monohydrate, m.p. 110°-112° C.

Examples 1B-1CR

Following a procedure similar to that described in Example 1A above, thefollowing species of formula I in Table 1 were prepared by reaction of a2-R₂ -3-R₃ -carbonyl-1H-indole of formula II with an appropriate haloalkylamine or tosyloxyalkylamine. The acid-acceptor and reaction solventused in the reactions are given in the column headed "Cat./Solv.". Hereand elsewhere in the tables, the form in which the product was isolated,either as the free base or as an acid-addition salt, is given in columnsheaded "Base/Salt", and the abbreviations "Morph.", "Pip." and "Pyr." inthe columns headed N=B represent the 4-morpholinyl, 1-piperidinyl and1-pyrrolidinyl groups, respectively. In Table 1, unless noted otherwise,an appropriate chloroalkylamine was used as the alkylating agent. Hereand elsewhere in the specification and the claims, the alkylene groups,Alk, are depicted as they would appear with the 1-indolyl moietyattached to the carbon atom at the left end of the alkylene chain andwith the amine group, N=B, attached to the carbon at the right end ofthe chain.

    TABLE 1      Example R.sub.2 R.sub.3 R.sub.4 Alk NB Cat./Solv. Base/Salt m.p./Solv.     Yield       1B CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 -- (CH.sub.2).sub.2 Morph.     K.sub.2 CO.sub.3 /DMF Base(c) 104-105/EtOAc-hexane 37 1C CH.sub.3     2-furyl -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 DMF HCl.H.sub.2 O     190-192/ether 35 1D CH.sub.3 4-CH.sub.3 SC.sub.6      H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3      /DMF Base 125-126/EtOAc-hexane 36 1E CH.sub.3 4-CH.sub.3 OC.sub.6     H.sub.4 7-CH.sub.3 (CH.sub.2).sub.2 Morph. NaH/DMF Base 149-151/i-PrOH     83 1F CH.sub.3 4-CH.sub.3 SOC.sub.6 H.sub.4 -- (CH.sub.2).sub.2 Morph.     K.sub.2 CO.sub.3 /DMF 1/4H.sub.2 O 103-105/EtOAc-hexane 68 1G CH.sub.3     4-CH.sub.3 OC.sub.6 H.sub.4 5-F (CH.sub.2).sub.2 Morph. NaH/DMF HCl     198-200/MeOH-ether 59 1H CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Morph. NaH/DMF HCl 248-249/MeOH-ether 53 1I CH.sub.3     4-CH.sub.3 OC.sub.6 H.sub.4 5-F (CH.sub.2).sub.3 Morph. NaH/DMF HCl     222-224/i-PrOH-ether 50 1J CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Morph. NaH/DMF HCl 202-203/i-PrOH-ether 53 1K CH.sub.3     4-CH.sub.3 OC.sub.6 H.sub.4 -- (CH.sub.2).sub.2 Pyr. NaH/DMF HCl     233-235/MeOH-ether 41 1L CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Pip. MaH/DMF CH.sub.3 SO.sub.3 H 228-230/MeOH-ether 31     1M CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 7-F (CH.sub.2).sub.2 Morph.     NaH/DMF Base 120-121/i-PrOH 23 1N CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4     7-CH.sub.3 O (CH.sub.2).sub.2 Morph. NaH/DMF HCl 203-204 25 1-O CH.sub.3     4-CH.sub.3 OC.sub.6 H.sub.4 6-Cl (CH.sub.2).sub.2 Morph. NaH/DMF Base     138-139/i-PrOH  3 1P CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 4-/6-F(d)     (CH.sub.2).sub.2 Morph. NaH/DMF Base 127-128/DMF 39 1Q CH.sub.3 4-FC.sub.     6 H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF CH.sub.3     SO.sub.3 H 209-211/i-PrOH 70      1R CH.sub.3     ##STR16##      -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.2 /DMF CH.sub.3 SO.sub.3 H     142-145/i-PrOH 33  1S CH.sub.3 2-benzo[b]furyl -- (CH.sub.2).sub.2     Morph. K.sub.2 CO.sub.3 /DMF CH.sub.3 SO.sub.3 H 194-198/EtOH 60 1T     CH.sub.3 3-benzo[b]thienyl -- (CH.sub.2).sub.2 Norph. K.sub.2 CO.sub.3     /DMF CH.sub.3 SO.sub.3 H.H.sub.2      O 155-158/EtOH 55 1U CH.sub.3 2-CH.sub.3 OC.sub.6      H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF CH.sub.3     SO.sub.3 H 199-214/i-PrOH 65 1V CH.sub.3 3-F-4-CH.sub.3 OC.sub.6 H.sub.4     -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF CH.sub.3 SO.sub.3 H(e)     130-135/i-PrOH 63 1W CH.sub.3 2-naphthyl -- (CH.sub.2).sub.2 Morph.     K.sub.2 CO.sub.3 /DMF CH.sub.3 SO.sub.3 H 195-198/i-PrOH 35 1X H     4-CH.sub.3 OC.sub.6 H.sub.4 5-CH.sub.3 (CH.sub.2).sub.2 Morph. K.sub.2     CO.sub.3 /DMF CH.sub.3 SO.sub.3      H 150-151/i-PrOH 45 1Y CH.sub.3 3-FC.sub.6 H.sub.4 -- (CH.sub.2).sub.2     Morph. K.sub.2 CO.sub.3      /DMF Base 130-131/i-PrOH 77 1Z CH.sub.3 2-FC.sub.6      H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3      /DMF Base 112-114/i-PrOH 65 1AA CH.sub.3 4-CNC.sub.6 H.sub.4 --     (CH.sub.2).sub.3 Morph. K.sub.2 CO.sub.3 /DMF CH.sub.3 SO.sub.3 H     198-200/i-PrOH 29 1AB CH.sub.3 C.sub.6      H.sub.5 4-CH.sub.3 (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF Base     116-117.5/EtOAc 46 1AC CH.sub.3 4-C.sub.2 H.sub.5 C.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF Base 124-126/EtOAc 70 1AD     CH.sub.3 3-NO.sub.2 C.sub.6 H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub.2     CO.sub.3 /DMF Base 141-143/EtOAc 67 1AE CH.sub.3 4-CH.sub.3 C.sub.6     H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3      /DMF Base 120.5-121.5/EtOAc 60 1AF CH.sub.3 4-CNC.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF Base 156.5-158.5/EtOAc 89     1AG CH.sub.3 4-C.sub.6 H.sub.5 CH.sub.2 OC.sub.6      H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3      /DMF Base 140-141/EtOH 69 1AH CH.sub.3 3-CH.sub.3 OC.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF Base 130-131/EtOAc 84 1AI     CH.sub.3 3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 -- (CH.sub.2).sub.2     Morph. K.sub.2 CO.sub.3 /DMF HCl 230-233/i-PrOH 64 1AJ C.sub.6 H.sub.5     4-CH.sub.3 OC.sub.6 H.sub.4 -- (CH.sub.2).sub.2 Morph. NaH/DMF Base     90-92 29 1AK H C.sub.6 H.sub.5 5-CH.sub.3 O (CH.sub.2).sub.2 Morph.     NaH/DMF Base 98-101 55 1AL CH.sub.3 C.sub.6 H.sub.5 5-CH.sub.3 O     (CH.sub.2).sub.2 Morph. NaH/DMF Base 88-90 50 1AM CH.sub.3 4-CH.sub.3     OC.sub.6 H.sub.4 6-CH.sub.3 O (CH.sub.2).sub.2 Morph. NaH/DMF HCl     222-224/EtOAc-MDC-ether 63 1AN CH.sub.3 4-NO.sub.2 C.sub.6 H.sub.4     6-CH.sub.3 O (CH.sub.2).sub.2 Morph. NaH/DMF Base 126-128 46 1AO     CH.sub.3 C.sub.6 H.sub.5 -- (CH.sub.2).sub.2 Morph. NaH/DMF Base     111-112/EtOAc-hexane 78 1AP H C.sub.6 H.sub.5 -- (CH.sub.2).sub.2 Morph.     NaH/DMF Base 101-103/EtOAc-hexane 69 1AQ CH.sub.3 4-ClC.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Morph. NaH/DMF Base 148-150/EtOAc 54 1AR H 4-ClC.sub.6     H.sub.4 -- (CH.sub.2).sub.2 Morph. NaH/DMF Base 136-138/EtOAc-hexane 60     1AS CH.sub.3 3,4-Cl.sub.2 C.sub.6 H.sub.3 -- (CH.sub.2).sub.2 Morph.     K.sub.2 CO.sub.3      /DMF Base 128-130/EtOAc-hexane 44 1AT CH.sub.3 2-thienyl -- (CH.sub.2).s     ub.2 Morph. K.sub.2 CO.sub.3 /DMF HCl 230-240/MeOHH.sub.2 O-ether 66 1AU     CH.sub.3 4-ClC.sub.6 H.sub.4 6-CH.sub.3 O (CH.sub.2).sub.2 Morph.     K.sub.2 CO.sub.3 /DMF HCl 275-285/EtOHH.sub.2      O 52 1AV CH.sub.3 2-thienyl 6-CH.sub.3 O (CH.sub.2).sub.2 Morph.     K.sub.2 CO.sub.3 /DMF HCl 224-228/EtOHH.sub.2 O 100  1AW CH.sub.3     C.sub.6 H.sub.5 -- CHCH.sub.3 CH.sub.2 Morph. K.sub.2 CO.sub.3 /DMF Base     137-139/EtOAc-hexane 1.3 1AX(f) CH.sub.3 C.sub.6 H.sub.5 -- CH.sub.2     CHCH.sub.3 Morph. K.sub.2 CO.sub.3 /DMF Base 108-110/EtOAc-hexane 48     1AY(g) H C.sub.6 H.sub.5 -- CHCH.sub.3 CH.sub.2 Morph. K.sub.2 CO.sub.3     /DMF Base 123-125/EtOAc-hexane  7 1AZ(g) H C.sub.6 H.sub.5 -- CH.sub.2     CHCH.sub.3 Morph. K.sub.2 CO.sub.3 /DMF Base 97-100/EtOAc-hexane 48 1BA     H C.sub.6 H.sub.5 7-CH.sub.3 (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3     /DMF Base 131-133/EtOAc-hexane 80 1BB CH.sub.3 1-naphthyl -- (CH.sub.2).s     ub.2 Morph. K.sub.2 CO.sub.3 /DMF Base 122-124/i-PrOH 40 1BC CH.sub.3     4-CNC.sub.6 H.sub.4 -- (CH.sub.2).sub.2 Pyr. NaH/DMF Base 138-139/i-PrOH     22 1BD CH.sub.3 4-CH.sub.3 OC.sub.6      H.sub.4 -- (CH.sub.2).sub.2 N(CH.sub.3).sub.2 NaH/DMF HCl 237-240/MeOH     56 1BE CH.sub.3 4-CH.sub.3 OC.sub.6      H.sub.4 -- (CH.sub.2).sub.2 N(C.sub.2 H.sub.5).sub.2 NaH/DMF HCl     209-211/EtOAc-ether 62 1BF CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Morph. NaH/DMF Base.1/4H.sub.2 O 127-128/DMF 38 1BG     CH.sub.3 4-PrOC.sub.6 H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub. 2     CO.sub.3 /DMF Base 104.5-105.5/EtOAc 39 1BH CH.sub.3 4-EtOC.sub.6     H.sub.4 -- (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3      /DMF Base 93-97/i-PrOH 68 1BI CH.sub.3 4-CH.sub.3 O-1-naphthyl --     (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF CH.sub.3 SO.sub.3 H.0.4     i-PrOH 145-147/i-PrOH 26 1BJ CH.sub.3 6-CH.sub.3 O-2-naphthyl --     (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF Base 159-160/EtOAc 4.9 1BK     CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 6-C.sub.6 H.sub.5 CH.sub.2 O     (CH.sub.2).sub.2 Morph. NaH/DMF Base EtOAc 46 1BL CH.sub.3 4-CNC.sub.6     H.sub.4 5-F (CH.sub.2).sub.3 Morph. NaH/DMF HCl.1/2H.sub.2      O 225-227/MeOH-ether 35 1BM H 4-CH.sub.3 OC.sub.6      H.sub.4 5-F (CH.sub.2).sub.3 Morph. NaH/DMF HCl 172-174/i-PrOH 67 1BN     CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 5-F (CH.sub.2).sub.3 Pip. NaH/DMF     HCl 199-201/MeOH-ether 40 1BO CH.sub.3 C.sub.6      H.sub.5 5-F (CH.sub.2).sub.3 Morph. NaH/DMF HCl 244-245/MeOH-ether 81     1BP CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 5-F (CH.sub.2).sub.3 N(C.sub.2     H.sub. 5).sub.2 NaH/DMF HCl 124-126/MeOH-ether 52 1BQ CH.sub.3 4-CH.sub.3      OC.sub.6      H.sub.4 5-Cl (CH.sub.2).sub.3 Morph. NaH/DMF HCl 160-162/MeOH-ether(h)     64 1BR CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 5,7-F (CH.sub.2).sub.3     Morph. NaH/DMF HCl 231-233/i-PrOH 79 1BS CH.sub.3 4-CH.sub.3 OC.sub.6     H.sub.4 7-F (CH.sub.2).sub.3 Morph. NaH/DMF HCl 209-211/MDC-ether 59 1BT     CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 5-F CHCH.sub.3 CH.sub.2 CH.sub.2     Morph. NaH/DMF HCl 178-180/i-PrOH-ether 72 1BU CH.sub.3 2-FC.sub.6     H.sub.4 -- CH.sub.2 CHCH.sub.3 Morph. NaH/DMF Base 107-109 53 1BV     CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 -- CH.sub.2 CHCH.sub.3 Morph.     NaH/DMF Base 128-130/EtOAc-hexane 45 1BW CH.sub.3 2-FC.sub.6 H.sub.4 5-F     CHCH.sub.3 CH.sub.2 CH.sub.2 Morph. NaH/DMF Base 124-126/EtOAc-hexane 50     1BX CH.sub.3 4-CNC.sub.6 H.sub.4 -- CHCH.sub.3 CH.sub.2 CH.sub.2 Morph.     NaH/DMF HCl 160-162/MeOH-ether 84 1BY CH.sub.3 4-CH.sub.3 OC.sub.6     H.sub.4 -- CHCH.sub.3 CH.sub.2      CH.sub.2 Morph. NaH/DMF HCl 164-166/MeOH-ether 24 1BZ CH.sub.3 4-C.sub.6      H.sub. 5 C.sub.6 H.sub.4 -- CH.sub.2 CH.sub.2 Morph. K.sub.2 CO.sub.3     /DMF Base 131.5-133/CH.sub.3 CN 59      1CA CH.sub.3     ##STR17##      -- CH.sub.2 CH.sub.2 Morph. K.sub.2 CO.sub.3      /DMF Base 173-174/CHCl.sub.3 81  1CB CH.sub.3 2-C.sub.6 H.sub.5 C.sub.6     H.sub.4 -- CH.sub.2 CH.sub.2 Morph. K.sub.2 CO.sub.3      /DMF HCl 130-138/ether 96 1CC CH.sub.3 4-CNC.sub.6 H.sub.4 5-F CH.sub.2     CH.sub.2 Morph. NaH/DMF HCl.1/2H.sub.2 O 212-214/MeOH 44 1CD CH.sub.3     2-FC.sub.6 H.sub.4 -- CHCH.sub.3 CH.sub.2 CH.sub.2 Morph. NaH/DMF     HCl.1/4H.sub.2 O 147-150/MDC-ether 36 1CE CH.sub.3 2-naphthyl --     CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2 NaH/DMF Base 106-107/EtOAc 34     1CF CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 -- (CH.sub.2).sub.3 Pyr.     NaH/DMF CH.sub.3 SO.sub.3 H 152-153/i-PrOH 77 1CG CH.sub.3 4-CH.sub.3     OC.sub.6 H.sub.4 -- (CH.sub.2).sub.3 Pyr. NaH/DMF CH.sub.3 SO.sub.3 H     125-126/i-PrOH 70 1CH H C.sub.6      H.sub.5 -- (CH.sub.2).sub.2 N(CH.sub.3).sub.2 NaH/DMF Base 65-67 43 1CI     CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 5-F (CH.sub.2).sub.5 Morph. NaH/DMF     HCl 175-176/EtOH-ether 11 1CJ CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4 5-F     (CH.sub.2).sub.4 Morph. NaH/DMF HCl 214-216/EtOH-ether 30 1CK CH.sub.3     2,3-F.sub.2 C.sub.6 H.sub.3 -- (CH.sub.2).sub.2 Morph. NaH/DMF Base     165-167/MDC 37 1CL CH.sub.3 2,6-(CH.sub.3).sub.2 C.sub.6 H.sub.3 --     (CH.sub.2).sub.2 Morph. NaH/DMF HCl 275-280 100       1CM CH.sub.3 2,3-(CH.sub.3 O).sub.2 C.sub.6      H.sub.3 -- (CH.sub.2).sub.2 Morph. NaH/DMF Base 126-128 77 1CN CH.sub.3     3,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 -- (CH.sub.2).sub.2 Morph.     NaH/DMF Base 88-90 64 1CO CH(CH.sub.3).sub.2 4-CH.sub.3 OC.sub.6 H.sub.4     -- (CH.sub.2).sub.2 Morph. NaH/DMF Base 151-153/EtOAc-ether 42 1CP     CH(CH.sub.3).sub.2 4-CH.sub.3 OC.sub.6 H.sub.4 5-F (CH.sub.2).sub.3     Morph. NaH/DMF Base 90-92 42 1CQ CH.sub. 3 4-NO.sub.2 C.sub.6 H.sub.4 --     (CH.sub.2).sub.2 Morph. K.sub.2 CO.sub.3 /DMF Base 173-175 49 1CR     CH.sub.3 1-naphthyl -- (CH.sub.2).sub.3 Morph. NaH/DMF Base 135-138/ether      50     (c)The corresponding methanesulfonate has m.p. 162-164 (from     isopropanolether); the hydrochloride, m.p. 178-182 (from water); the     fumarate, m.p. 184-187 (from methanolether); and the maleate, 146-149     (from methanol ether). A higher melting polymorph of the maleate, m.p.     163-166, was obtained on crystallization from methanol alone.     (d)Consists of a 4:1 mixture of the 4fluoro and 6fluoro isomers.     (e)Contains 0.4 mole of isopropanol.     (f)Prepared by reaction of 4(2-tosyloxypropyl) morpholine with appropriat     indole.     (g)Prepared by reaction of 4(bromopropyl)morpholine with appropriate     indole.     (h)A higher melting polymorph of the hydrochloride has m.p. 217-218 from     isopropanol.

From the Compounds of Formula III

Example 2A

To a stirred, refluxing solution of 13.2 g. (0.054 mole) of1-[1-methyl-2-(4-morpholinyl)ethyl]-1H-indole (Preparation 5B) in 150ml. of ethylene dichloride was added, over a period of about one hour, amixture of 17.35 g. (0.13 mole) of aluminum chloride and 10.08 g. (0.065mole) of 4-methylbenzoyl chloride in 200 ml. of ethylene dichloride.When addition was complete, the mixture was heated under reflux under anitrogen atmosphere for three and a half hours and then poured, withstirring, into 1 liter of ice and water containing 300 ml. of 5N sodiumhydroxide. The mixture was transferred to a separatory funnel, theorganic layer was separated, and the aqueous layer was washed with anadditional 300 ml. of ethylene dichloride. The combined organic extractswere then washed with brine, filtered, dried over magnesium sulfate,filtered again and evaporated to dryness to give a viscous oil (22.55g.) which solidified on cooling. The latter was recrystallized, aftercharcoaling, from isopropanol to give 15.78 g. (81%) of3-(4-methylbenzoyl)-1-[1-methyl-2-(4-morpholinyl) ethyl]-1H-indole, m.p.116.5°-1118° C.

Examples 2B-2BI

Following a procedure similar to that described in Example 2A above, thefollowing species of formula I in Table 2 below were prepared byreaction of a 2-R₂ -1-aminoalkyl-1H-indole of formula III with anappropriate acid chloride (R₃ CO-Cl) in the presence of aluminumchloride. The solvent used to carry out the reaction, methylenedichloride (MDC) or ethylene dichloride (EDC), is given in the columnheaded "Solv."

                                      TABLE 2                                     __________________________________________________________________________    Ex-                                                                           ample                                                                             R.sub.2                                                                          R.sub.3   R.sub.4                                                                            Alk    N═B                                                                           Solv.                                                                             Base/Salt                                                                             m.p./Solv.   Yield               __________________________________________________________________________    2B  CH.sub.3                                                                         4-CH.sub.3 C.sub.6 H.sub.4                                                              --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base    163-165/i-PrOH                                                                             69                  2C  CH.sub.3                                                                         2-FC.sub.6 H.sub.4                                                                      --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base    126-128/i-PrOH                                                                             62                  2D  H  4-FC.sub.6 H.sub.4                                                                      --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base    153-155/i-PrOH                                                                             83                  2E  H  2-FC.sub.6 H.sub.4                                                                      --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base    145-147/i-PrOH                                                                             65                  2F  H  N--CH.sub.3 -2-pyrrolyl                                                                 --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC HCl     142-144/i-PrOH                                                                             20                  2G  CH.sub.3                                                                         4-FC.sub.6 H.sub.4                                                                      --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base    95-98/heptane                                                                              23                  2H  CH.sub.3                                                                         N--CH.sub.3 -2-pyrrolyl                                                                 --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base    143-145/i-PrOH                                                                             32                  2I  CH.sub.3                                                                         4-CH.sub.3 OC.sub.6 H.sub.4                                                             --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base(i) yellow-orange                                                                              13                                                               powder                           2J  H  C.sub.6 H.sub.5                                                                         7-CH.sub.3                                                                         CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC HCl.1/2C.sub.2 H.sub.5 OH                                                             amorphous,   62                                                               off white solid                  2K  CH.sub.3                                                                         4-NO.sub.2 C.sub.6 H.sub.4                                                              --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base    oil          59                  2L  CH.sub.3                                                                         2-CNC.sub.6 H.sub.4                                                                     --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC maleate 185-186      19                  2M  CH.sub.3                                                                         3-CNC.sub.6 H.sub.4                                                                     --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    122-124      26                  2N  CH.sub.3                                                                         N--CH.sub.3 -3-pyrrolyl                                                                 --   (CH.sub.2).sub.2                                                                     Morph.                                                                            EDC HCl     235-240/CH.sub.3 CN                                                                        16                  2-O CH.sub.3                                                                         4-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4                                                     --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    174-175/MDC-ether                                                                          47                  2P  CH.sub.3                                                                         3-thienyl --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC HCl     225-227/H.sub.2 O                                                                          39                  2Q  CH.sub.3                                                                         cyclohexyl                                                                              --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    138-139/EtOH 44                  2R  CH.sub.3                                                                         4-t-C.sub.4 H.sub.9 C.sub.6 H.sub.4                                                     --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC HCl     235-236      57                  2S  CH.sub.3                                                                         2-benzo[b]-thienyl                                                                      --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    134-135      23                  2T  CH.sub.3                                                                         N--CH.sub.3 -2-pyrrolyl                                                                 --   (CH.sub.2).sub.2                                                                     Morph.                                                                            EDC HCl     238-240/acetone                                                                            18                  2U  CH.sub.3                                                                         2-CH.sub.3 C.sub.6 H.sub.4                                                              --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC HCl     245-247/i-PrOH-ether                                                                       25                  2V  CH.sub.3                                                                         3,4-(CH.sub.3).sub.2 C.sub.6 H.sub.4                                                    --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    145-147/i-PrOH                                                                             41                  2W  CH.sub.3                                                                         C.sub.6 H.sub.5 CH═CH.sub.2                                                         --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    127-128/EtOH 29                  2X  CH.sub.3                                                                         3-benzo[b]furyl                                                                         --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    134-135/EtOH 28                  2Y  H  2-CH.sub.3 C.sub.6 H.sub.4                                                              --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    129-131/i-PrOH                                                                             100                 2Z  CH.sub.3                                                                         4-CH.sub.3 O-cyclohexyl                                                                 --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    110-112/cyclohexane                                                                        16                  2AA C.sub.2 H.sub.5                                                                  4-CH.sub.3 OC.sub.6 H.sub.4                                                             --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    143-145.5/EtOAc-ether                                                                      88                  2AB Cl 4-CH.sub.3 OC.sub.6 H.sub.4                                                             --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC HCl     170-173/EtOH 58                  2AC CH.sub.3                                                                         4-C.sub.3 H.sub.7 C.sub.6 H.sub.4                                                       --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    86.5-87.5/EtOAc-ether                                                                      68                  2AD CH.sub.3                                                                         2-CH.sub.3 C.sub.6 H.sub.4                                                              5-F  (CH.sub.2).sub.3                                                                     Morph.                                                                            MDC HCl     215.5-219.5/EtOH                                                                           76                  2AE CH.sub.3                                                                         4-FC.sub.6 H.sub.4                                                                      5-F  (CH.sub.2).sub.3                                                                     Morph.                                                                            MDC HCl     223.0-225.0/EtOH                                                                           43                  2AF CH.sub.3                                                                         3-furyl   5-F  (CH.sub.2).sub.3                                                                     Morph.                                                                            MDC HCl     211.0-214.0/EtOH                                                                           46                  2AG CH.sub.3                                                                         C.sub.6 H.sub.5 CH═CH                                                               5-F  (CH.sub.2).sub.3                                                                     Morph.                                                                            MDC HCl     223.5-226.5/MeOH                                                                           44                  2AH CH.sub.3                                                                         2,4-F.sub.2 C.sub.6 H.sub.3                                                             5-F  (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    118-120/i-PrOH                                                                             24                  2AI CH.sub.3                                                                         2-FC.sub.6 H.sub.4                                                                      --   CHC.sub.2 H.sub.5 CH.sub.2                                                           Morph.                                                                            MDC Base    162-165/EtOAc-hexane                                                                       52                  2AJ CH.sub.3                                                                         4-CH.sub.3 OC.sub.6 H.sub.4                                                             --   CHC.sub.2 H.sub.5 CH.sub.2                                                           Morph.                                                                            MDC HCl     153-157/i-PrOH-ether                                                                       39                  2AK CH.sub.3                                                                         1-naphthyl                                                                              --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Maleate 87/t-butyl methyl                                                                          36her               2AL H  1-naphthyl                                                                              --   (CH.sub.2).sub.2                                                                     Morph.                                                                            EDC Base    105-107/ether                                                                              44                  2AM CH.sub.3                                                                         5-benzo[b]furyl                                                                         --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    165.5-167/EtOAc-acetone                                                                    46                  2AN CH.sub.3                                                                         2,4-F.sub.2 C.sub.6 H.sub.3                                                             --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    121-123.5/i-PrOH                                                                           30                  2AO CH.sub.3                                                                         2,4-F.sub.2 C.sub.6 H.sub.3                                                             5-F  (CH.sub.2).sub.3                                                                     Morph.                                                                            EDC HCl     212-216/EtOH 33                  2AP CH.sub.3                                                                         2-F-4-CH.sub.3 OC.sub.6 H.sub.3                                                         --   (CH.sub.2).sub.2                                                                     Morph.                                                                            EDC HCl     258-260/EtOH 25                  2AQ CH.sub.3                                                                         2-F-4-CH.sub.3 OC.sub.6 H.sub.3                                                         5-F  (CH.sub.2).sub.3                                                                     Morph.                                                                            EDC HCl     221-223.5/EtOH                                                                             16                  2AR CH.sub.3                                                                         4-BrC.sub.6 H.sub.4                                                                     5-F  (CH.sub.2).sub.3                                                                     Morph.                                                                            MDC HCl     238-240/i-PrOH                                                                             64                  2AS CH.sub.3                                                                         2,6-F.sub.2 C.sub.6 H.sub.3                                                             --   (CH.sub.2).sub.2                                                                     Morph.                                                                            EDC Base    117-119/EtOAc                                                                              53                  2AT CH.sub.3                                                                         2,3-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                    --   (CH.sub.2).sub.2                                                                     Morph.                                                                            EDC HCl.3/4H.sub.2 O                                                                      241-243/EtOH 35                  2AU CH.sub.3                                                                         3,5-Cl.sub.2 C.sub.6 H.sub.3                                                            --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    145-146      55                  2AV CH.sub.3                                                                         3,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                    --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    142-144/EtOH-hexane                                                                        51                  2AW CH.sub.3                                                                         3-CH.sub.3 C.sub.6 H.sub.4                                                              --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    125-127      44                  2AX CH.sub.3                                                                         3-ClC.sub.6 H.sub.4                                                                     --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    116-118/EtOAc-ether                                                                        38                  2AY CH.sub.3                                                                         3-FC.sub.6 H.sub.4                                                                      --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC Base    85-87        27                  2AZ CH.sub.3                                                                         2-ClC.sub.6 H.sub.4                                                                     --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC HCl     150(dec.)/EtOAc                                                                            37                  2BA CH.sub.3                                                                         1-naphthyl                                                                              7-CH.sub.3 O                                                                       (CH.sub.2).sub.2                                                                     Morph.                                                                            EDC Base    225-227/EtOAc-ether                                                                        11                  2BB CH.sub.3                                                                         2-FC.sub.6 H.sub.4                                                                      5-F  (CH.sub.2).sub.3                                                                     Morph.                                                                            MDC HCl     224-226/EtOH 20                  2BC CH.sub.3                                                                         3-furyl   --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC HCl     243-245/EtOH-ether                                                                         21                  2BD CH.sub.3                                                                         2-FC.sub.6 H.sub.4                                                                      5-F  CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            MDC HCl     208-211/EtOAc                                                                              49                  2BE CH.sub.3                                                                         4-BrC.sub.6 H.sub.4                                                                     --   (CH.sub.2).sub.2                                                                     Morph.                                                                            EDC HCl.1/2H.sub.2 O                                                                      257-260      13                  2BF CH.sub.3                                                                         5-(1H-benzimid-                                                                         --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    173.5-175.5/EtOAc                                                                          25                         azolyl)                                                                2BG CH.sub.3                                                                         4-Br-1-naphthyl                                                                         --   (CH.sub.2).sub.2                                                                     Morph.                                                                            MDC Base    126.5-128.5/EtOAc-ether                                                                    35                  2BH H  4-CH.sub.3 OC.sub. 6 H.sub.4                                                            --   CHCH.sub.3 CH.sub.2                                                                  Morph.                                                                            EDC HCl.H.sub.2 O                                                                         140          54                  2BI CH.sub.3                                                                         2-naphthyl                                                                              --   CHC.sub.2 H.sub.5 CH.sub.2                                                           Morph.                                                                            MDC CH.sub.3 SO.sub.3 H                                                                   214-216/i-PrOH                                                                             32                  __________________________________________________________________________     (i) The hydrochloride has m.p. 193-197 (from methanolt-butyl methyl           ether).                                                                  

C. From the Compounds of Formula VI

Example 3A

A solution of 10 g. (0.022 mole) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(p-toluenesulfonyloxy)ethyl]-1H-indole (Preparation 7A) and 8.74 g. (0.086 mole) of4-hydroxypiperidine in 50 ml. of dry acetonitrile was heated underreflux for about forty eight hours, and the mixture was then dilutedwith ethyl acetate and washed with water. The organic layer wasextracted with 2N hydrochloric acid, then with water, and the combinedaqueous washings were combined, basified with 10% sodium hydroxide andextracted with ethyl acetate. The combined organic extracts were driedover magnesium sulfate, filtered and concentrated to dryness to give theproduct, in the form of the free base, as a brown oil. The latter wasconverted to the hydrochloride salt in ethyl acetate and etherealhydrogen chloride to give 2.6 g. (27%) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-hydroxy-1-piperidinyl)ethyl]-1H-indolehydrochloride hemihydrate, m.p. 226°-229° C.

Examples 3B-3AM

Following a procedure similar to that described in Example 3A above, thefollowing species of formula I in Table 3 below were prepared byreaction of a 2-methyl-3-R₃ -carbonyl-1-(2-tosyloxyethyl)-1H-indole or a2methyl-3-R₃ -carbonyl-1-(halo-lower-alkyl)-1H-indole of formula VI withan appropriate amine, HN=B, where R₂, in each instance, is CH₃. Thestarting material in each of Examples 3B-3V, 3AK and 3AM was thecorresponding 1-(2-tosyloxyethyl)-1H-indole; in Example 3W thecorresponding 1-(3-chloropropyl)-1H-indole; and in each of Examples3X-3AJ and 3AL the corresponding 1-(bromo-lower-alkyl)-1H-indole.

                                      TABLE 3                                     __________________________________________________________________________    Example                                                                            R.sub.3                                                                              R.sub.4                                                                           Alk  N═B     Solv.                                                                              Base/Salt                                                                              m.p./Solv.  Yield              __________________________________________________________________________    3B   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   3-HO-1-piperidinyl                                                                        CH.sub.3 CN                                                                        HCl.1/2H.sub.2 O(j)                                                                    160         31                 3C   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   4-CH.sub.3 -1-piperazinyl                                                                 CH.sub.3 CN                                                                        Base     110-112     28                 3D   4-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                    --  (CH.sub.2).sub.2                                                                   3-HO-1-piperidinyl                                                                        CH.sub.3 CN                                                                        Base     139-141     57                 3E   4-CNC.sub.6 H.sub.4                                                                  --  (CH.sub.2).sub.2                                                                   3-HO-1-piperidinyl                                                                        DMF  HCl      225-227/MeOH-ether                                                                        59                 3F   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   3-HO-1-pyrrolidinyl                                                                       DMF  HCl      188-190/i-PrOH                                                                            65                 3G   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   N(CH.sub.2 CH.sub.2 OH).sub.2                                                             DMF  Base     105-107/EtOAc                                                                             30                 3H   1-naphthyl                                                                           --  (CH.sub.2).sub.2                                                                   3-HO-1-piperidinyl                                                                        DMF  HCl.H.sub.2 O.                                                                         175-180/i-PrOH-ether                                                                      24                                                       1/6 i-PrOH                              3I   1-naphthyl                                                                           --  (CH.sub.2).sub.2                                                                   1-piperazinyl                                                                             DMSO 2HCl     237.5-241/MeOH                                                                            38                 3J   1-naphthyl                                                                           --  (CH.sub.2).sub.2                                                                   4-CH.sub.3 -1-piperazinyl                                                                 DMF  2HCl.1/2H.sub.2 O                                                                      195.5-199.5/MeOH                                                                          27                 3K   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   NHC.sub.2 H.sub.5                                                                         DMF  maleate  180-181/EtOH                                                                              50                 3L   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   NHCH.sub.2 CH.sub.2 OCH.sub.3                                                             DMF  maleate  166-168/EtOH                                                                              47                 3M   1-naphthyl                                                                           --  (CH.sub.2).sub.2                                                                   2-CH.sub.3 -4-morpholinyl                                                                 DMF  Base     144-145/ether                                                                             21                 3N   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   3-CH.sub.3 CONH-1-                                                                        DMF  Base     122-130/EtOAc                                                                             32                                      piperidinyl                                              3-O  4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   N(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                           DMF  maleate  137.5-140/MeOH-ether                                                                      21                 3P   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   2-CH.sub.3 -4-morpholinyl                                                                 DMF  maleate.1/2EtOAc                                                                       135-140/EtOAc                                                                             52                 3Q   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   2-cyclohexylmethyl-1-                                                                     DMF  maleate  209.5-210.5/CH.sub.3                                                                      42                                      piperidinyl                                              3R   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   2,6-di-CH.sub.3 -4-                                                                       DMF  maleate  162-162.5/acetone                                                                         36                                      morpholinyl                                              3S   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   4-CHO-1-piperazinyl(k)                                                                    DMF  Base     163-165/EtOAc                                                                             43                 3T   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   1-(1,4-diazepinyl)(l)                                                                     DMF  2CH.sub.3 SO.sub.3 H                                                                   200-202     100                3U   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   Thiomorph.  DMF  Base     124-125/EtOAc                                                                             50                 3V   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   Thiomorph.-S,S-dioxide                                                                    DMF  maleate  181-182/CH.sub.3 CN                                                                       15                 3W   4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F (CH.sub.2).sub.3                                                                   3-HO-1-piperidinyl                                                                        DMF  HCl      126-128/MeOH-ether                                                                        69                 3X   1-naphthyl                                                                           --  (CH.sub.2).sub.3                                                                   1-pyrrolidinyl                                                                            DMF  HCl.1/2H.sub.2 O                                                                       150-157/acetone                                                                           78                 3Y   4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F (CH.sub.2).sub.3                                                                   2-CH.sub.3 -4-morpholinyl                                                                 DMF  HCl      216-217/i-PrOH                                                                            85                 3Z   4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.3                                                                   1-piperidinyl                                                                             DMF  HCl      201-203/i-PrOH-ether                                                                      80                 3AA  4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.4                                                                   4-morpholinyl                                                                             DMF  HCl      208-211/CH.sub.3 CN-ether                                                                 43                 3AB  4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.4                                                                   1-piperidinyl                                                                             DMF  HCl      238-241/CH.sub.3                                                                          24-ether           3AC  4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.4                                                                   1-pyrrolidinyl                                                                            DMF  HCl      181-183/CH.sub.3 CN-ether                                                                 36                 3AD  4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.4                                                                   N(C.sub.2 H.sub.5).sub.2                                                                  DMF  HCl      176-177/CH.sub.3 CN-ether                                                                 50                 3AE  4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.3                                                                   N(C.sub.2 H.sub.5).sub.2                                                                  DMF  HCl      179-181/CH.sub.3 CN                                                                       11                 3AF  4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F (CH.sub.2).sub.3                                                                   Thiomorph.  DMF  HCl      238-241     84                 3AG  4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F (CH.sub.2).sub.3                                                                   NHC.sub.2 H.sub.5                                                                         DMF  p-Tosylate                                                                             149-150/EtOH                                                                              28                 3AH  4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F (CH.sub.2).sub.3                                                                   Thiomorph.-S,S-dioxide                                                                    DMF  HCl      153-155/EtOH                                                                              54                 3AI  4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F (CH.sub.2).sub.3                                                                   4-CH.sub.3 -1-piperazinyl                                                                 DMF  maleate  195-197/MeOH                                                                              100                3AJ  4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F (CH.sub.2).sub.3                                                                   N(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                           DMF  Base     118-120/EtOAc                                                                             100                3AK  4-CH.sub.3 OC.sub.6 H.sub.4                                                          --  (CH.sub.2).sub.2                                                                   N(CHO)CH.sub.2 CH.sub.2 OH(k)                                                             DMF  Base     glass       81                 3AL  4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F (CH.sub.2).sub.3                                                                   4-CHO-1-piperazinyl                                                                       DMF  Base     oil         31                 3AM  1-naphthyl                                                                           --  (CH.sub.2).sub.2                                                                   1-piperidinyl                                                                             DMF  Base     119-121/EtOH                                                                              32                 __________________________________________________________________________     (j) The anhydrous hydrochloride has m.p. 224-226 (from ethanol).              (k) The product became formylated at the secondary amine group of the         N═B function by the DMF solvent under the reaction conditions used.       (l) 1,4Diazepine used as the H--N═B reactant. As in Example 3S, the       product became formylated on the 4position of the diazepine by the DMF        solvent. The crude 4formyl product was then saponified by heating for six     hours in a solution of 6.14 g. of sodium hydroxide in 300 ml. of ethanol      and 240 ml. of water.                                                    

D. Miscellaneous Processes

Example 4A

Following a procedure similar to that described inPreparation3above,8.0g. (0.02 mole)of2-methyl-3-(3-nitrobenzoyl)-1-[2-(4-morpholinyl) ethyl]-1H-indole(Example 1AD) in 175 ml. of ethyl acetate and 75 ml. of acetic acid wasreduced with hydrogen in a Parr shaker over 0.3 g. of platinum oxide.The product was isolated in the form of the free base and recrystallizedfrom ethyl acetate to give 6.0 g. (83%) of2-methyl-3-(3-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p.167°-169° C.

Example 4B

Following a procedure similar to that described in Example 4A above, 289. (0.07 mole) of 2-methyl-3-(4-nitrobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole (Example 1CQ) in 100 ml. of 91acial acetic acid and 100ml. of ethyl acetate was reduced with hydrogen over platinum oxide andthe product, in the form of the free base, was recrystallized from ethylacetate to give 19.05 g. (75%) of2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl) ethyl]-1H-indole, m.p.154°-156° C.

A small amount of the free base was reacted with methanesulfonic acidand the product recrystallized from ethanol to give the correspondingmethanesulfonate as an orange powder, m.p. 221°-223° C.

Example 4C

To a stirred suspension of 2.5 g. (0.0059 mole) of2-methyl-3-(4-nitrobenzoyl)-6-methoxy-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1AN) and 2 g. (0.036 mole) of iron filings in 25 ml. of 50%aqueous ethanol in a three-necked flask equipped with a reflux condenserand a stirrer was added, over a five minute period with stirring, 0.93ml. of a solution containing 5 ml. of concentrated hydrochloric acid in25 ml. of 50% aqueous ethanol. When addition was complete, the reactionmixture was heated under reflux for two and a half hours, then cooledand made basic with 15% alcoholic potassium hydroxide solution. Themixture was filtered, the filtrate was taken to dryness in vacuo, andthe oily product was dissolved in methylene dichloride and the organicsolution washed first with alkali, then with water and then with brineand dried over magnesium sulfate. Filtration of the solution andconcentration to dryness afforded an oil which, on trituration withethyl acetate/diethyl ether, crystallized to give 1.4 g. (71%) of2-methyl-3-[4-aminobenzoyl)-6-methoxy-1-[2-(4-morpholinyl)ethyl]-1H-indole,m.p. 126°-128° C.

Example 4D

Following a procedure similar to that described in Example 4C above, 7.3g. (0.018 mole) of2-methyl3-(4-nitrobenzoyl)-1-[1-methyl-2-(4-morpholinyl)ethyl]-1H-indole(Example 2K), dissolved in 75 ml. of 50% ethanol, was reduced with 6 g.(0.11 mole) of iron filings and 2.8 ml. of a solution containing 5.2 ml.of concentrated hydrochloric acid in 25 ml. of 50% ethanol. The productwas isolated in the form of the free base to give 3.7 g. (54%) of2-methyl-3-(4-aminobenzoyl)-1-[1-methyl-2-(4-morpholinyl)ethyl]-1H-indole,m.p. 192°-195° C.

Example 5A

To a solution of 4.0 g. (0.01 mole) of2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 4B) in 20 ml. of glacial acetic acid was added 2.3 ml. (0.023mole) of acetic anhydride and 2 drops of concentrated sulfuric acid. Themixture was warmed slightly, then poured into water and the aqueousmixture basified by addition of 10% sodium hydroxide. The gum whichseparated was isolated by decantation, triturated with water to producea solid material which was collected and recrystallized from ethylacetate to give 2.3 g. (56%) of2-methyl3-(4-acetylaminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole,m.p. 173.5°-174.5° C.

Examples 5B-5F

Following a procedure similar to that described in Example 5A above, thefollowing compounds of formula I in Table 5 below were prepared byacylation of an appropriate2-methyl-3-(aminobenzoyl)-1-aminoalkyl-1H-indole. In each instance, R₂is CH₃ ; R₄ is hydrogen; Alk is (CH₂)₂ ; and N=B is 4-morpholinyl. Allcompounds were isolated and characterized as the free bases. Theacylating agent and the reaction solvent are given in the column headed"AcX/Solv."

                                      TABLE 5                                     __________________________________________________________________________    Example                                                                            R.sub.3   AcX/Solv.  m.p./Solv.                                                                              Yield                                     __________________________________________________________________________    5B   3-CH.sub.3 CONHC.sub.6 H.sub.4                                                          Ac.sub.2 O/HOAc                                                                          165-166/toluene                                                                         44                                        5C   4-CF.sub.3 CONHC.sub.6 H.sub.4                                                          (CF.sub.3 CO).sub.2 O/MDC                                                                170-172/toluene                                                                         38                                        5D   4-C.sub.6 H.sub.5 CONHC.sub.6 H.sub.4                                                   C.sub.6 H.sub.5 COCl/MDC(m)                                                              148-149/MeOH                                                                            69                                        5E   4-CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4                                                   CH.sub.3 SO.sub.2 Cl/MDC(n)                                                              225-227/MeOH(o)                                                                         14                                        5F   4-C.sub.2 H.sub.5 CONHC.sub.6 H.sub.4                                                   C.sub.2 H.sub.5 COCl/HOAc                                                                144-145/EtOAc                                                                           13                                        __________________________________________________________________________     (m) Potassium carbonate used as acid acceptor.                                (n) Triethylamine used as acidacceptor.                                       (o) Corresponds to the trihydrate.                                       

Example 6

Following a procedure similar to that described in Preparation 3 above,14.0 g. (0.03 mole) of2-methyl-3-(4-benzyloxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1AG) in 250 ml. of ethanol was reduced with hydrogen in a Parrshaker over 1.0 g. of 5% palladium-on-charcoal. The product wasconverted to the hydrochloride salt which was recrystallized from waterto give 11.1 g. (92%) of2-methyl-3-(4-hydroxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indolehydrochloride, m.p. 286°-288° C.

Example 7

A mixture of 7.5 g. (0.02 mole) of2-methyl-3-(4-cyanobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1AF), 100 ml. of ethanol, 15 ml. of liquid ammonia and 2tablespoons of a Raney nickel in ethanol suspension was heated in anautoclave at 50° C. under an initial hydrogen pressure of 320 p.s.i.g.The mixture was then cooled, the catalyst was removed by filtration, andthe solution was taken to dryness in vacuo to give 7.2 g. of product asa green foamy material which was converted to the hydrochloride salt togive 1.7 g. (19%) of2-methyl-3-(4-aminomethylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indoledihydrochloride, m.p. 196°-208° C.

Example 8A

A mixture of 10.4 g. (0.023 mole) of2-methyl-3-[4-(N-trifluoroacetylamino)benzoyl]-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 5C), 20 g. (0.20 mole) of potassium carbonate and 5 ml. (11.4g., 0.08 mole) of methyl iodide in 100 ml. of acetone was heated underreflux with stirring for two hours and then taken to dryness to yield ayellow foam, which was partitioned between water and chloroform andextracted twice with chloroform. The combined extracts were washed withbrine, filtered and taken to dryness to give a yellow oil which wasdissolved in isopropanol and treated with excess hydrogen chloridefollowed by additional isopropanol. The solution was diluted with ether,and the solid which separated was collected and dried to give 4.6 g. of2-methyl-3-[4-(N-methyl-N-trifluoroacetylamino)benzoyl]-1-[20(4-morpholinyl)-ethyl]-1H-indolehydrochloride, m.p. 224°-226° C.

The latter (3.7 g., 0.007 mole) was mixed with 25 ml. of 10% sodiumhydroxide, and the mixture was heated under reflux for one hour. Oncooling, a solid separated from the mixture which was collected,dissolved in isopropanol and treated with excess hydrogen chloride andisopropanol. The solid which separated was collected and recrystallizedfrom methanol/diethyl ether to give 1.2 g. (37%) of2-methyl-3-(4-methylaminobenzoyl)-1-[2-(4-morpholinyl)-ethyl]-1H-indoledihydrochloride hemihydrate, m.p. 190°-192° C.

Example 8B

Following a procedure similar to that described in Example 8A, 22 g.(0.049 mole) of2-methyl-3-[4-(N-trifluoroacetylamino)benzoyl]-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 5C) was reacted with 35.9 g. (0.129 mole) of butyl iodide in250 ml. of acetone in the presence of 48 g. (0.343 mole) of potassiumcarbonate and the resulting2-methyl-3-[4-(N-butyl-N-trifluoroacetylamino)benzoyl]-1-[2-(4-morpholinyl)ethyl]-1H-indole(24 g., 98%) hydrolyzed by refluxing in a solution of 500 ml. of 10%sodium hydroxide and 100 ml. of ethanol. The resulting crude product waschromatographed on silica gel, eluting with 25% acetone-hexane. Thehigher R_(f) material was collected and dried to give 2.6 g. of2-methyl-3-(4-butylaminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole,m.p. 129.0°-130.0° C.

Example 9

To a stirred suspension of 12.0 g. (0.03 mole) of2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 4B) in 15 ml. of glacial acetic acid and 30 ml. of water wasadded a solution of 4.5 g. (0.06 mole) of sodium isocyanate in 30 ml. ofwater. The mixture was stirred at room temperature for two hours, thendiluted with water and made alkaline with 10% sodium hydroxide. Thesolid which separated was collected and recrystallized from DMF to give5.9 g. (48%) of2-methyl-3-(4-carbamylaminobenzoyl)-1-[2-(4-morpholinyl)ethyll]-1H-indole,m.p. 192°-202° C.

Example 10

To a stirred suspension of 3.77 g. (0.01 mole) of2-methyl-3-(4-aminomethylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 7) in 30 ml. of toluene was added a solution of dimethylcyanocarbonimidodithioate in 20 ml. of toluene. The mixture was stirredfor an hour and a half, and the solid which separated was collected anddried to give 4.75 g. of the corresponding3-(4-aminomethylbenzoyl)-N-(methyl cyanocarbonimidothioate).

The latter (4.0 g., 0.008 mole), in 75 ml of isopropanol and 25 ml ofliquid ammonia, was heated in an autoclave for one hour at 100° C. Thereaction mixture was then filtered, allowed to evaporate to dryness, andthe resulting pale yellow foam was recrystallized from acetonitrile togive 2.3 g. (65%) of2-methyl-3-(4-cyanoguanidinylmethylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole,m.p. 191.5°-195° C.

Example 11

A mixture of 10 g. (0.027 mole) of2-methyl-3-(4-cyanobenzoyl)-1-[2-(4-morpholinyl) ethyl]-1H-indole(Example 1AF), 20 g. (0.19 mole) of sodium hypophosphite, 50 ml. ofwater, 50 ml. of glacial acetic acid, 100 ml. of pyridine and twospatulas of Raney nickel was heated to about 40° C. for two and a halfhours and then filtered. The filtrate was taken to dryness in vacuo, andthe resulting oil was washed with toluene and again concentrated todryness to remove residual pyridine. The residual oil was suspended inaqueous alkali and extracted with ethyl acetate. The combined organicextracts was washed with brine, dried over magnesium sulfate, filteredand concentrated to dryness to give an oil which was recrystallized fromethyl acetate to afford 1.5 g. (15%) of2-methyl-3-(4-formylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p.149°-150° C.

Example 12

A mixture of 2.5 g. (0.006 mole) of2-methyl-3-(4-formylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 11), 0.55 g. (0.0067 ) mole of sodium acetate and 0.51 g.(0.0073 mole) of hydroxylamine hydrochloride in 24 ml. of ethanol, 5 ml.of methanol and 6 ml. of water was heated under reflux for one hour andthen concentrated to dryness in vacuo. The residual solid was collected,washed with water and diethyl ether to give 2.5 g. (95%) of2-methyl-3-(4-oximinomethylenebenzoly)-1-[2-(4-morpoholinyl)-ethyl]-1H-indole,m.p., 184°-186° C.

Example 13A

A mixture of 20 g. (0.053 mole) of2-methyl-3(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1B) and 20 g. (0.29 mole) of hydroxylamine hydrochloride in 100ml. of pyridine was heated under reflux for about twelve hours and thendiluted with methylene dichloride. The organic mixture was washed fivetimes with water, then with brine, dried over magnesium sulfate,filtered and taken to dryness in vacuo to give a dark green oil whichwas washed three times with toluene and again concentrated to dryness invacuo. Trituration of the residue with ethyl acetate/diethyl etherafforded crystals which were collected to give 9.5 g. (46%) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indoleoxime, m.p. 166°-169° C.

Example 13B

Following a procedure similar to that described in Example 13A above, 44g. (0.101 mole) of5-fluoro-3-(2-fluorobenzoyl)-2-methyl-1-[3-(4-morpholinyl)propyl]-1H-indole(Example 2BB) was reacted with 70.3 g. (1.01 moles) of hydroxylaminehydrochloride in 500 ml of pyridine and the product recrystallized fromacetonitrile to give 15.5 g. (37%) of5-fluoro-3-(2-fluorobenzoyl)-2-methyl-1-[3-(4morpholinyl)propyl]-1H-indoleoxime, m.p. 150°-162° C.

Example 13C

Following a procedure similar to that described in Example 13A above, intwo runs a total of 28.3 g. (0.77 mole) of3-(2-fluorobenzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1Z) was reacted with a total of 53.7 g. (0.77 mole) ofhydroxylamine hydrochloride in a total of 575 ml. of pyridine to give atotal of 24.4 g. of crude product. The latter was dissolved in asolution of 54.1 g. of sodium methoxide in 500 ml. of methanol, and thesolution was heated under reflux for forty-eight hours and then taken todryness in vacuo. The residue was partitioned between chloroform andwater, and the chloroformsoluble material was flash chromatographed onsilica gel eluting with 98:2 chloroform:isopropanol. The slower movingmaterial was isolated and recrystallized from toluenehexane to give 8.0g. (33%) of(E)-3-(2-fluorobenzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indoleoxime, m.p. 160°-167° C.

Example 14

A mixture of 8 g. (0.022 mole) of2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 4B) and 4.28 ml. (0.033 mole) of 2,5-dimethoxytetrahydrofuranin 40 ml. of glacial acetic acid was heated under reflux for one hourand then poured into an ice/water mixture. The mixture was renderedalkaline by addition of 10% sodium bicarbonate solution, and the solidwhich separated was collected and dissolved in methylene dichloride. Theorganic solution was dried over magnesium sulfate, filtered and thefiltrate concentrated to dryness in vacuo and then chromatographedthrough a pad of Florisil, eluting with methylene dichloride. There wasthus obtained 4.5 g. of an oil which, on trituration with diethyl ether,afforded a light yellow powder which was collected to give 3.5 g. (38%)of 2-methyl-3-[4-(1H-pyrrol-1-yl)benzoyl]-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p. 125°-127° C.

Example 15

To each of three 14 liter fermentors containing 10 liters of soybeanmeal/dextrose medium (containing 5 g./ liter of soybean meal, 5 g./literof brewer's yeast, 5 g./ liter of dipotassium hydrogen phosphate and 20g./liter of dextrose) at pH 6.4, was added 2.0 g. (0.016 mole total) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1B), and the mixtures were cultured for five days in thepresence of Fusarium solani (Mart.) with stirring at 400 rpm at atemperature of 26°-27° C. while sparging with air at 5 liters perminute. The mixtures were then separately extracted with 20 liters ofmethylene dichloride using 20 liters per fermentor, and the combinedextracts were concentrated to 20 liters. The concentrate was washedfirst with 2 liters of 0.05N sodium hydroxide, then two times with 2liters of water, and the organic layer was concentrated to about 1liter, dried over sodium sulfate, charcoaled, filtered and furtherevaporated to dryness to give an oily residue which solidified oncooling. The latter was recrystallized from acetone/diethyl ether togive 2.7 g. (43%) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole/N(MOR)-oxide,m.p. 142°-144° C.

Example 16A

A mixture of 38.3 g. (0.10 mole) of2-methyl-3-(2-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1U) and 35.2 g. (0.31 mole) of pyridine hydrochloride washeated in an oil bath at 210° C. for four hours and the mixture allowedto cool. The solidified reaction mixture was partitioned between ethylacetate and aqueous sodium carbonate by warming on a steam bath, and theorganic layer was separated, taken to dryness and subjected to highperformance liquid chromatography on a silica gel column in 1:1hexane:ethyl acetate. The first 7 liters of eluate were discarded, andthe next 8 liters were collected, taken to dryness and the residuerecrystallized from isopropanol to give 8.33 g. (23%) of2-methyl-3-(2-hydroxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p.115°-116° C.

Example 16B

Following a procedure similar to that described in Example 16A, 15.8 g.(0.035 mole) of5-fluoro-2-methyl-3(4-methoxybenzoyl)-1-[3-(4-morpholinyl)propyl]-1H-indolehydrochloride (Example 1I) was heated with 20.4 g. (0.176 mole) ofpyridine hydrochloride at 210° C. in an oil bath for two hours, and theproduct isolated as the hydrochloride salt to give 9.2 g. (67%) of5-fluoro-2-methyl-3(4-hydroxybenzoyl)-1-[3-(4-morpholinyl)propyl]-1H-indolehydrochloride, m.p. 290°-292° C. (from DMF-ether).

Example 17

A mixture of 1.9 g. (0.005 mole) of2-methyl-3(4-aminomethylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 7), 0.7 g. (0.0025 mole) of 2-methyl-2-thiopseudourea sulfateand 10 ml of water was heated on a steam bath for two hours and thenfiltered. The filtrate was taken to dryness, and the residue wasrecrystallized from methanol to give 1.0 g. (85%) of2-methyl-3-(4-guanidinylmethylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indolesulfate (2:1), m.p. 170°-180° C.

Example 18

Following a procedure similar to that described in Preparation 3 above,a solution of 0.9 g. (0.0019 mole) of6-benzyloxy-2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1BK) in 200 ml. of methanol was reduced with hydrogen overthree spatulas (approximately 1.5 g.) of 10% palladium-on-charcoal undera hydrogen pressure of 50 p.s.i.g. at ambient temperature in a Parrshaker. The product was isolated in the form of the hydrochloride whichwas recrystallized from ethyl acetatediethyl ether to give 0.35 g. of6-hydroxy-2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indolehydrochloride hydrate (3:4), m.p. 185°-187° C.

Example 19

To 70 ml. of dry DMF was added, dropwise with stirring, 15 ml. ofphosphorus oxychloride while cooling in an ice bath. The mixture wasthen treated with a solution of 24.4 g. (0.10 mole) of2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole (Preparation 4A) in 50 ml.of DMF while continuing to cool in an ice bath. When addition wascomplete, the mixture was stirred for about one hour and then pouredinto 50 g. of ice to give a clear solution which was chilled to about20° C. and basified by the addition of 150 ml. of 35% potassiumhydroxide. The mixture was warmed to about 70°, then chilled in an icebath, and the solid which separated was collected, dried andrecrystallized from ethyl acetate to give 23.3 g. (86%) of3-formyl-2-methyl-1[2-(4-morpholinyl) ethyl]-1H-indole, m.p. 115°-116°C.

A solution containing 13.6 g. (0.05 mole) of the latter and 9.0 g. (0.06mole) of 4-methoxyacetophenone in 50 ml. of absolute ethanol was treatedwith 500 ml. of 3.7N ethanolic hydrogen chloride in a thin stream, whilestirring, and the resulting red solution was stirred for twenty-fourhours. The solid which separated was collected by filtration, washedwith absolute ethanol and then recrystallized first from methanol andthen from 50% ethanol to give 5.3 g. (24%) of1-{2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl}-3-(4-methoxyphenyl)propen-3-onemonohydrochloride, m.p. 259°-262° C.

Example 20A

Following a procedure similar to that described in Example 19 above,3-acetyl-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole was prepared byreaction of 12 g. (0.05 mole) of2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole (Preparation 4A) with 10ml. (0.11 mole) of phosphorus oxychloride in 25 ml. ofdimethylacetamide. The product was dissolved in isopropanol and thesolution treated with ethereal hydrogen chloride to give 6 g. (37%) ofthe product as the hydrochloride salt, m.p. 249°-253 ° C.

To a solution of 6 g. (0.107 mole) of potassium hydroxide pellets in 350ml. of absolute ethanol was added 15 g. (0.047 mole) of the latter and19 g. (0.14 mole) of 2-methylbenzaldehyde. The mixture was heated underreflux for one and a half hours, concentrated to dryness and theproduct, in the form of the free base, recrystallized once from ethylacetate and once from isopropanol to give 7.9 g. (41%) of3-(2-methylcinnamoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole,m.p. 131°-135° C.

Example 20B

Following a procedure similar to that described in Example 20A above,14.75 g. (0.0516 mole) of3-acetyl-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole (Example 20A) wasreacted with 2-fluorobenzaldehyde in 260 ml. of ethanol in the presenceof 3.44 g. (0.061 mole) of potassium hydroxide pellets and the product,in the form of the free base, recrystallized from ethyl acetate to give10.0 g. (54%) of3-(2-fluorocinnamoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole,m.p. 113°-116° C.

Example 21

A solution of 11 g. (0.025 mole) of1-[2-(3-hydroxy-1-piperidinyl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indole(Example 3B) in 50 ml. of pyridine and 25 ml. of acetic anhydride wasallowed to stand at ambient temperature for about forty-eight hours andthe mixture then poured into ice water. The oily solid which separatedwas collected, dissolved in ethyl acetate and the solution washed firstwith dilute sodium hydroxide, then with brine, dried and taken todryness. The residue was dissolved in ethyl acetate, the solutiontreated with 3.67 g. of maleic acid, the mixture heated to boiling todissolve all solid, then cooled, and the solid which separated wascollected and recrystallized once again from ethyl acetate to give 8.12g. (59%) of1-[2-(3-acetoxy-1-piperidinyl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indolemaleate (1:1), m.p. 161°-161.5° C.

Example 22

To a stirred solution of 12.5 g. (0.03 mole) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(1-piperazinyl)ethyl]-1H-indole(Example 1L) in 150 ml. of pyridine was added, with stirring whilecooling in an ice bath, 7.1 g. (0.066 mole) of ethyl chloroformate. Whenaddition was complete, the solution was stirred in an ice bath forthirty minutes, then allowed to stand at ambient temperature for abouteighteen hours and then poured into ice water. Extraction of the mixturewith ethyl acetate afforded the crude product in the form of the freebase which was dissolved in ethyl acetate and converted to the maleatesalt by addition of 2.6 g. of maleic acid. The latter was recrystallizedfrom ethyl acetate-ether to give 7.6 g. (41%) of 1-[2-(4-carbethoxy-1-piperazinyl)ethyl]-2-methyl-3-(4-methoxybenzoyl) -1H-indole maleate(1:1), m.p. 155°-156° C.

Example 23A

A solution of 12.5 g. (0.033 mole) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(1-piperazinyl)ethyl]-1H-indole(Example 1L) in 150 ml. of pyridine was cooled in an ice bath andtreated with 50 ml. of acetic anhydride and the solution allowed tostand at ambient temperature for about eighteen hours. The solution wasthen poured into ice water and the mixture extracted with ethyl acetate.The organic solution, on washing with brine, drying over sodium sulfateand evaporation to dryness, afforded the crude product which was takeninto ethyl acetate and the solution treated with 4.2 g. of maleic acid.The solid which separated was collected and recrystallized from ethanolto give 7.36 g. (42%) of1-[2-(4-acetyl-1-piperazinyl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indolemaleate (1:1), m.p. 147.5°-152° C.

Example 23B

Following a procedure similar to that described above in Example 23A,11.9 g. (0.029 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[3-(1-piperazinyl)propyl]-1H-indole (Example1BN) was reacted with 50 ml. of acetic anhydride in 150 ml. of pyridineand the product isolated in the form of the methanesulfonate salt togive 6.6 g. (41%) of5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[3-(4-acetyl-1-piperazinyl)propyl]-1H-indolemethanesulfonate, m.p. 170°-171° C.

Example 24

A solution of 15 g. (0.04 mole) of2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 4B), 12 g. (0.4 mole) of formaldehyde and 7.5 g. (0.119 mole)of sodium cyanoborohydride in 250 ml. of acetonitrile was stirred forthirty minutes and then treated dropwise with acetic acid until acidic.The mixture was stirred for about eighteen hours, then poured intoaqueous potassium hydroxide and the mixture extracted with ether. Theorganic extracts, on drying over magnesium sulfate and concentration todryness, afforded a yellow solid which was recrystallized fromisopropanol to give 7.5 g. (48%) of3-(4-dimethylaminobenzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole,m.p. 152°-154° C.

Example 25A

A solution of 19.1 g. (0.047 mole) of1-(3-bromopropyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1H-indole(Preparation 7D) in 500 ml. of acetone and 50 ml. of water was treatedwith 3.05 g. (0.047 mole) of sodium azide and the mixture heated underreflux for about eighteen hours and then taken to dryness in vacuo. Theresidue was partitioned between ethyl acetate and water, and the organiclayer separated, washed with brine, taken to dryness and the residuerecrystallized from isopropanol to give 10.3 g. (60%) of1-(3-azidopropyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1H-indole, m.p.69-73.

The latter (0.028 mole) was dissolved in 265 ml. of ethanol and 35 ml.of THF and reduced with hydrogen over 1.0 g. of 10%palladium-on-charcoal in a Parr shaker. When reduction was complete, inabout four hours, the mixture was filtered, the filtrate taken todryness and the residue dissolved in ethyl acetate and treated with 3.13g. of maleic acid and heated to dissolve all the material. The solidwhich separated was collected and recrystallized from isopropanol togive 9.7 g. (76%) of1-(3-aminopropyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1H-indolemaleate (1:1) m.p. 169°-171° C.

Example 25B

Following a procedure similar to that described in Example 25A above,13.98 g. (0.03 mole) of2-methyl-3-(4-methoxybenzoyl)-1-(2-tosyloxyethyl)-1H-indole (Preparation7A) in 325 ml. of acetone and 32.5 ml. of water was reacted with 1.96 g.(0.03 mole) of sodium azide and the product recrystallized fromisopropanol to give 6.1 g. (61%) of1-(2-azidoethyl)-2-methyl-3-(4-methoxybenzoyl)-1H-indole, m.p. 91°-93°C.

The latter (0.024 mole), dissolved in 250 ml. of ethanol and 50 ml. ofTHF, was reduced with hydrogen over 0.8 g. of 10% palladium-on-charcoalat 47 p.s.i.g. and the product isolated in the form of the maleate saltto give 7.6 g. (75%) of 1-(2-aminoethyl)-2-methyl-3-(4-methoxybenzoyl)-1H-indole maleate, m.p. 165°-166° C.

Example 26A

A mixture of 10 g. (0.027 mole) of3-(4-fluorobenzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole,(Example 1Q) 2.5 g. (0.033 mole) of 2-methoxyethylamine and 7.6 g.(0.054 mole) of potassium carbonate in 15 ml. of DMSO was heated at 95°C. under nitrogen and the mixture then poured into ice water. The solidwhich separated was collected, dissolved in methylene dichloride and thesolution washed with brine, dried over magnesium sulfate, filtered andtaken to dryness in vacuo. Recrystallization of the residue from ethylacetate-ether afforded 4.2 g. (37%) of2-methyl-3-[4-(2-methoxyethylamino)benzoyl]-1-[2-(4-morpholinyl)ethyl]-1H-indole,m.p. 121°-123° C.

Examples 26B-26I

Following a procedure similar to that described in Example 26A above,reaction of a3-(4-halobenzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole with anappropriate amine in the presence of potassium carbonate afforded thespecies of formula I in Table 26 where, in each instance, R₂ is CH₃ ;and N=B is 4-morpholinyl. The species of Examples 26B-26D, 26G and 26Hwere obtained from the corresponding 4-fluorobenzoyl starting material,and the species of Examples 26E, 26F and 26I were obtained from thecorresponding bromobenzoyl (or bromonaphthyl) starting materials.

                                      TABLE 26                                    __________________________________________________________________________    Example                                                                            R.sub.3 CO     R.sub.4                                                                          Alk Solv.                                                                             Base/Salt                                                                             m.p./Solv.                                                                              Yield                        __________________________________________________________________________    26B  4-(3-HO-1-piperdinyl)benzoyl                                                                 -- (CH.sub.2).sub.2                                                                  DMSO                                                                              2HCl.1/2H.sub.2 O                                                                     196       33                           26C  4-(1-piperazinyl)benzoyl                                                                     -- (CH.sub.2).sub.2                                                                  DMSO                                                                              2HCl.1/2H.sub.2 O                                                                     240       52                           26D  4-(4-HO-1-piperdinyl)benzoyl                                                                 -- (CH.sub.2).sub.2                                                                  DMSO                                                                              2HCl.1/2H.sub.2 O                                                                     130/EtOH-MDC                                                                            37                           26E  4-(1H-imidazol-1-yl)benzoyl                                                                  -- (CH.sub.2).sub.2                                                                  DMF Base    171-173/i-PrOH                                                                          54                           26F  4-(1H-imidazol-1-yl)benzoyl                                                                  5-F                                                                              (CH.sub.2).sub.3                                                                  DMF Base    135-137/i-PrOH                                                                          66                           26G  4-(4-morpholinyl)benzoyl                                                                     -- (CH.sub.2).sub.2                                                                  DMSO                                                                              HCl.H.sub.2 O                                                                         175/EtoAc-ether                                                                         43                           26H  4[HO(CH.sub.2).sub.3 NH]benzoyl                                                              -- (CH.sub.2).sub.2                                                                  DMSO                                                                              Base    122-124/EtOAc                                                                           32                           26I  4-CN-1-naphthyl-CO(p)                                                                        -- (CH.sub.2).sub.2                                                                  DMF Base    180.5-183.5/EtOAc                                                                       57                           __________________________________________________________________________     (p) Obtained from corresponding 4bromo-1-naphthyl species (Example 2AT)       and cuprous cyanide in presence of 5 drops of pyridine.                  

Example 27A

A mixture of 8.2 g. (0.02 mole) of1-[2-(4-formyl-1piperazinyl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indole(Example 3S) and 2.06 g. (0.052 mole) of sodium hydroxide in 100 ml. ofethanol and 80 ml. of water was heated under reflux for four hours, thenpoured into ice water and extracted with ethyl acetate. The organicsolution was washed with brine, dried over sodium sulfate, taken todryness and the residue dissolved in ethyl acetate. The solution wastreated with an excess of a 1N solution of methanesulfonic acid, and thesolid which separated was collected and recrystallized from ethanol togive 9.0 g. (79%) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(1-piperazinyl)ethyl]-1H-indoledimethanesulfonate, m.p. 240° C.

Examples 27B-27D

Following a procedure similar to that described in Example 26A above,the following species of formula I were similarly prepared:

Example 27B -1-[2-(2-hydroxyethylamino)ethyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indole,m.p. 99°-100.5° C. (14.2g., 50%), prepared by saponification of 30.8 g.(0.08 mole) of1-[2-(N-formyl-2-hydroxyethylamino)ethyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indole (Example 3AK) with 9.7 g. (0.243 mole) of sodium hydroxide in160 ml. of water and 200 ml. of ethanol;

Example 27C -1-[2-(3-amino-1-piperidinyl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indolemaleate (1:2), m.p. 142.5°-144° C. (1.5 g., 49%), prepared bysaponification of 1.6 g. (0.0026 mole) of1-[2-(3-acetylamino-1-piperidinyl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indole (Example 3N) with 1.6 g. (0.04mole) of sodium hydroxide in 2 ml. of water and 6 ml. of ethyleneglycol; and

Example 27D -5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[3-(1-piperazinyl)propyl]-1H-indoledimethanesulfonate, m.p. 114°-115° C. (8.7 g., 27%), prepared bysaponification of 23 g. (0.053 mole) of5-fluoro-1-[3-(4-formyl-1-piperazinyl)propyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indole(Example 3AL) with 5.6 g. (0.014 mole) of sodium hydroxide in 265 ml. ofethanol and 210 ml. of water.

Example 28

To a solution containing 16.9 g. (0.044 mole) of1(3-bromopropyl)-2-methyl-3-(4-methoxybenzoyl)-1H-indole (Preparation7G) in 200 ml. of DMF was added 5 g. (0.088 mole) of azetidine. Themixture was stirred for about 24 hours at ambient temperature, thendiluted with water and extracted with ethyl acetate. The organicextracts were washed with water, then with brine, dried over magnesiumsulfate, filtered and taken to dryness. The residue was taken into ethylacetate, the solution diluted with ethereal hydrogen chloride, and thesolid which separated was collected and recrystallized repeatedly fromisopropanol to give 2.0 g. (10%) of1-[3-(3-chloropropylamino)propyl]-2-methyl-3-(4-methoxybenzoyl)-1H-indolehydrochloride, m.p. 140°-142° C.

Example 29A

To a solution of 15.0 g. (0.032 mole) of5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[3-(4-thiomorpholinyl)propyl]-1H-indolehydrochloride (Example 3AF) in 195 ml. of glacial acetic acid was added8.12 g. (0.038 mole) of an 80% solution of m-chloroperbenzoic acid, andthe solution was stirred at ambient temperature for about forty-eighthours and then poured into 300 ml. of ice water. The mixture was treatedwith 1 g. of sodium bisulphite, basified with 35% sodium hydroxide andthen extracted with chloroform. The organic extracts, on washing withwater, then with brine, drying over sodium sulfate and evaporation todryness afforded 1.9 g. of the product as the free base which wasconverted to the maleate salt by solution of the base in ethyl acetateand addition of one equivalent of maleic acid. The salt wasrecrystallized from ethanol to give 12.85 g. (72%) of5-fluoro-2-methyl-3-(4-methoxybenzoyl)1-[3-(4-thiomorpholinyl)propyl]-1H-indoleS-oxide maleate, m.p. 160°-161° C.

Examples 29B and 29C

Following a procedure similar to that described in Example 29A above,the following species of formula I were similarly prepared:

Example 29B -2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-thiomorpholinyl)ethyl]-1H-indoleS-oxide maleate, m.p. 179°-180° C. (7.2 g., 82%), prepared by oxidationof 110 g. (0.028 mole) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-thiomorpholinyl)ethyl]-1H-indole(Example 3U) with 6.7 g. (0.03 mole) of m-chloroperbenzoic acid in 110ml. of glacial acetic acid; and

Example 29C -2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-thiomorpholinyl)ethyl]-1H-indoleS,N-dioxide dihydrate, m.p. 143°-145° C. (3.9 g., 27%), prepared byoxidation of 12.0 g. (0.030 mole) of2-methyl-3-(4-methoxybenzoyl)-1-[2-(4thiomorpholinyl)ethyl]-1H-indole(Example 3U) with 6.6 g. (0.030 mole) of m-chloroperbenzoic acid in 120ml. of chloroform.

Example 30

A solution of 28.7 g. (0.177 mole) of benzoylacetone and 23.2 ml. (0.177mole) of 2-(4-morpholinyl)ethylamine in 600 ml. of toluene was heatedunder reflux for ten and a half hours under a Dean-Stark trap and thesolution then cooled and taken to dryness to giveN-[2-(4morpholinyl)ethyl]-N-(1-methyl-3-oxo-3-phenylpropenyl)amine as ayellow solid.

The latter (11.3 g., 0.41 mole) and 8.9 g. (0.082 mole) of benzoquinonein 40 ml. of nitromethane was stirred under nitrogen for forty-eighthours at room temperature and the mixture then filtered through silicagel and the filtrate adsorbed onto silica gel and flash chromatographedusing 5% acetone in ethyl acetate. The product was taken off in theearly and middle fractions which were taken to dryness. The product wasrecrystallized first from ethyl acetate and then from methanol to give1.0 g. (7%) of3-benzoyl-5-hydroxy-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p.215°-217° C.

Example 31A

A solution of 12.4 g. (0.0395 mole) of5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[1-(2,3-epoxy)propyl]-1H-indole(Preparation 9A) and 4.79 g. (0.055 mole) of morpholine in 60 ml. ofchloroform was heated under reflux for about forty-eight hours and thentaken to dryness in vacuo. The crude product was dissolved in methylenedichloride, and the solution was treated with an excess of etherealhydrogen chloride and then diluted with ether. The solid which separatedwas collected and recrystallized from methanol-ether to give 13.3 g.(61%) of1-[2-hydroxy-3-(4-morpholinyl)propyl]-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1H-indolehydrochloride hydrate, (1HCl.l 1 1/4H₂ O), m.p. 143°-145° C.

Examples 31B-31-O

Following a procedure similar to that described in Example 31A above,reaction of a 1-[1-(2,3-epoxy)propyl]3-R₃ -carbonyl-1H-indole with anamine, HN=B, afforded the following compounds of formula Ib listed inTable 31, where R₂ in each instance is CH₃.

                                      TABLE 31                                    __________________________________________________________________________    Example                                                                            R.sub.3                                                                              R.sub.4                                                                          N═B Solv.                                                                              Base/Salt                                                                           m.p./Solv.   Yield                          __________________________________________________________________________    31B  4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F                                                                              1-piperidinyl                                                                         CHCl.sub.3                                                                         HCl   219-221/MeOH-ether                                                                         67                             31C  4-CH.sub.3 OC.sub.6 H.sub.4                                                          5-F                                                                              1-pyrrolidinyl                                                                        CHCl.sub.3                                                                         HCl   183-185/i-PrOH-ether                                                                       76                             31D  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- NHCH.sub.3                                                                            DMF  Base  104.5-106.5/EtOAc-EtOH                                                                     55                             31E  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- NHC(CH.sub.3).sub.3                                                                   DMF  Base  110-111.5/ether                                                                            63                             31F  1-naphthyl                                                                           -- 1-pyrrolidinyl                                                                        DMF  Base  161-162/EtOAc                                                                              88                             31G  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- Morph.  CHCl.sub.3                                                                         Base  88-90/EtOAc-hexane                                                                         32                             31H  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- 1-pyrrolidinyl                                                                        CHCl.sub.3                                                                         CH.sub.3 SO.sub.3 H                                                                 176-178/i-PrOH                                                                             37                             31I  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- 1-piperidinyl                                                                         CHCl.sub.3                                                                         Base  88-90/EtOAc-hexane                                                                         19                             31J  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- azido   acetone                                                                            Base  110-111/i-PrOH                                                                             38                             31K  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- 1-azetidinyl(q)                                                                       THF  Base  83-86/EtOAc-hexane                                                                          3                             31L  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- N(CH.sub.3).sub. 2                                                                    DMF  HCl   149-151/CH.sub.3 CN-ether                                                                  79                             31M  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- NHCH(CH.sub.3).sub.2                                                                  DMF  HCl   213-216/CH.sub.3 CN                                                                        68                             31N  4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- NHCH.sub.2 H.sub.5                                                                    DMF  Base  133-135/EtOAc-hexane                                                                       55                             31-O 4-CH.sub.3 OC.sub.6 H.sub.4                                                          -- N(C.sub.2 H.sub.5).sub.2                                                              DMF  Base  114-116/EtOAc-hexane                                                                       75                             __________________________________________________________________________     (q) The azetidine in the THF was first reacted with a 20% molar excess of     nbutyl lithium at 0° C., and the lithium salt thus formed was          treated with the epoxide in THF.                                         

Example 32

Following a procedure similar to that described above in Example 25A, 60g. (0.165 mole) of1-(3-azido-2-hydroxy-1-propyl)-2-methyl-3-(4-methoxybenzoyl)-1H-indole(Example 31J) in 500 ml. of ethanol was reduced with hydrogen over 35 g.of palladium-on-barium sulfate catalyst. The product was isolated in theform of the free base and recrystallized from ethyl acetate to give 10.2g. (18%) of1-(3-amino-2-hydroxy-1-propyl)-2-methyl-3-(4-methoxybenzoyl)-1H-indole,m.p. 152°-153° C.

Example 33

The hydrobromide salt of2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole(Example 1B) (10.0 g., 0.026 mole) was prepared by passing hydrogenbromide gas into a solution of the former in 200 ml. of MDC. Thehydrobromide was isolated, redissolved in 300 ml. of MDC and thesolution treated with 6.94 g. (0.039 mole) of N-bromosuccinimide. Thesolution was heated under reflux and irradiated with light for twentyminutes, and the solid which had separated was taken intochloroformethyl acetate and the solution extracted with aqueouspotassium carbonate, dried over magnesium sulfate and taken to dryness.The residue was chromatographed on silica gel, the product being elutedwith 25% acetone in toluene, which was isolated and recrystallized fromtoluene to give 3.7 g. (31%) of5-bromo-2-methyl-3-(4-methylbenzoyl)-1-[2-(4morpholinyl)ethyl]-1H-indole,m.p. 134.5°-136° C.

Examples 34A-34H

Following a procedure similar to that described in Example 2A above, itis contemplated that other species of formula I as follows can beprepared by reaction of a 2-R₂ -1-[2-(4-morpholinyl)ethyl]-1H-indolewith an appropriate aroyl chloride (R₃ COCl) in the presence of aluminumchloride in methylene dichloride:

Example 34A -2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(2-quinolinecarbonyl)-1H-indole,by reaction of 2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole with2-quinoline carboxylic acid chloride;

Example 34B -2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(3-quinolinecarbonyl)-1H-indole,by reaction of 2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole with3-quinoline carboxylic acid chloride;

Example 34C 2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(4-quinolinecarbonyl)-1H-indole, by reaction of2-methyl-1[2-(4-morpholinyl)ethyl]-1H-indole with 4-quinoline carboxylicacid chloride;

Example 34D - 2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(5-quinolinecarbonyl)-1H-indole, by reaction of2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole with 5-quinolinecarboxylic acid chloride;

Example 34E -2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(6-quinolinecarbonyl)-1H-indole,by reaction of 2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole with6-quinoline carboxylic acid chloride;

Example 34F -2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(7-quinolinecarbonyl)-1H-indole,prepared by reaction of 2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indolewith 7-quinoline carboxylic acid chloride;

Example 34G -2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(8-quinolinecarbonyl)-1H-indole,by reaction of 2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole with8-quinoline carboxylic acid chloride; and

Example 34H -2-benzoyl-1-[2-[4-morpholinyl)ethyl]-3-(4-methoxybenzoyl)-1H-indole, byreaction of 2-benzoyl-1-[2-(4-morpholinyl)ethyl]-1H-indole with4-methoxybenzoyl chloride.

BIOLOGICAL TEST RESULTS

The 3-R₃ -carbonyl-1-aminoalkyl-1H-indoles of formulas I, Ia and Ib ofthe invention were tested in the acetylcholine-induced abdominalconstriction test (Ach), the anti-bradykinin test (BRDK) and the rat pawflexion test (P.F.), all in vivo tests, and were found to have analgesicactivity. Data so-obtained are given in Table B below. Unless notedotherwise, all data were obtained on oral administration and areexpressed either as the ED₅₀ or as the percent inhibition at a givendose level (thus 30/100 or 30% inhibition at 100 mg./kg.)

In some instances, the compounds were retested two or more times, andED₅₀ values were calculated for each series of repeat tests. In suchinstances, each of the ED₅₀ values so-obtained is given in a series ofvalues, thus 6, 28, 30, 43 in the case of the species of Example 1AW inthe acetylcholine-induced abdominal constriction test.

                  TABLE B                                                         ______________________________________                                        Example   Ach         BRDK        P.F.                                        ______________________________________                                        1A        73          56                                                      1B        24.50.30,37 8.1 (i.v.)                                                        41,26,34,58                                                                   6.7 (i.v.)                                                                    21,48 (s.c.)                                                        1C        126                                                                 1D        34,10,54,22 0/100       64                                                    5.1 (i.v.)                                                                    49 (s.c.)                                                           1E        0/100                                                               1F        20          0/200       88/100                                                13 (i.v.)                                                           1G        84                                                                            0/3 (i.v.)                                                                    50/10 (i.v.)                                                                  100/30 (i.v.)                                                       1H        33/100                                                                        71/300                                                                        0/3 (i.v.)                                                                    30/10 (i.v.)                                                                  100/30 (i.v.)                                                                 2/30 (s.c.)                                                         1I        75                                                                            8.5 (i.v.)                                                          1J        86                                                                            6.7 (i.v.)                                                          1K        255                                                                           1-0/1 (i.v.)                                                                  30/3 (i.v.)                                                                   25/5.5 (i.v.)                                                                 44/10 (i.v.)                                                        1M        50/100                                                              1N        35.8                                                                1-0       91.6                                                                1P        40/100                                                                        4.5 (i.v.)                                                          1Q        7/24                                                                          27/79                                                                         60/238                                                                        67/435                                                                        60/793                                                                        67/1000                                                             1R        198                                                                 1S        40          162                                                               10/1 (i.v.)                                                                   20/3 (i.v.)                                                                   100/10 (i.v.)                                                       1T        106                                                                           3.8 (i.v.)                                                          1U        155                                                                 1V        20/300                                                              1W        0/30                                                                          40/300                                                                        47/550                                                                        10/1 (i.v.)                                                                   0/1.73 (i.v.)                                                                 86/3 (i.v.)                                                         1X        7/300                                                               1Y        30/100                                                              1Z        68                                                                  1AA       10/100                                                              1AB       47/300                                                              1AC       30          0/200       43/30                                                 10/1.77 (i.v.)          57/50                                                 10/2./2 (i.v.)          75/100                                                80/3 (i.v.)                                                                   100/10 (i.v.)                                                       1AE       29          20/300      66.2                                        1AF       200                                                                           0/3 (i.v.)                                                                    0/10 (i.v.)                                                                   30/30 (i.v.)                                                        1AG       40/100                                                                        47/300                                                                        10/10 (i.v.)                                                                  56/30 (i.v.)                                                                  20/30 (s.c.)                                                        1AH       85                                                                  1AI       74                                                                  1AJ       13/100                                                                        53/300                                                              1AK       40/300                                                                        47/550                                                              1AL       113                                                                 1AM       32                                                                            5 (i.v.)                                                            1AO       28          111         75/100                                      1AP       42          0/50                                                                          33/200                                                                        60/400                                                  1AQ       53/300                  0/10                                                  17 (i.v.)               12/30                                                                         12/100                                      1AR       27/150                                                                        27/300                                                                        13/25 (s.c.)                                                        1AS       33/300                                                              1AT       30          0/50,200                                                1AU       42          0/50                                                    1AV       38          0/50                                                    1AW       6,28,30,43  229         26                                          1AX       45          0/212                                                   1AY       11,37,49    141         0/30,100                                              8.5 (i.v.)              20/300                                      1AZ       10,27/50                                                                      20/75                                                                         73/100                                                                        53/150                                                              1BA       197                                                                 1BB       97                                                                  1BC       40/100                                                              1BD       65                                                                  1BE       50.9                                                                1BF       0/30                                                                1BG       33/300                                                              1BH       0/30                                                                          27/100                                                                        53/300                                                                        58/550                                                                        7/30 (s.c.)                                                                   50/10 (i.v.)                                                        1BI       13/300      0/6                                                               27/100 (s.c.)                                                                 0.69 (i.v.)                                                         1BJ       0/100                                                               1BL       0/100                                                               1BM       0/100                                                               1BN       36                                                                  1BO       173                                                                 1BP       28                                                                  1BR       123                                                                 1BT       90/100                                                              1BW       10/100                                                              1BZ       0/100                                                               1CA       20/100                                                              1CB       60/100                                                              1CC       10/100                                                              1CD       79                                                                  1CE       0/100                                                               1CF       24                                                                  1CG       46.3                                                                1CH       105                                                                 1CI       70/100                                                              1CJ       56                                                                  1CK       30/100                                                              1CL       30/100                                                              2A        7/30                                                                          60/300                                                                        73/550                                                                        67/1000                                                             2B        47/300                                                                        33/550                                                              2C        19,33       0/30                                                              3.3 (i.v.)  60/300                                                  2D        20/100                                                                        40/300                                                                        67/1000                                                             2E        33                                                                  2F        20/30                                                                         40/100                                                                        33/300                                                              2G        42                                                                  2H        49                                                                  2I        28          132         62/100                                                2.6 (i.v.)                                                                    18 (s.c.)                                                           2J        60                                                                  2L        10/100                                                              2M        20/100                                                              2N        20/100                                                              2-O       20/100                                                              2P        30/100                                                              2Q        20/100                                                              2R        10/100                                                              2S        0/100                                                               2T        30/100                                                              2U        88                                                                  2V        20/100                                                              2W        72                                                                  2AB       91                                                                  2AC       30/100                                                              2AD       10/100                                                              2AE       20/100                                                              2AF       30/100                                                              2AG       143                                                                 2AH       20/100                                                              2AK       30/0.3 (i.v.)                                                       2AL       20/0.1 (i.v.)                                                       2AM       80/100                                                              2AN       90                                                                  2AO       40/100                                                              2AP       27                                                                  2AR       50/100                                                              2AT       20/100                                                              2AU       30/100                                                              2AV       10/100                                                              2AW       20/100                                                              2AX       0/100                                                               2AZ       26                                                                  2BB       40/100                                                              2BC       10/100                                                              2BD       15                                                                  2BE       30/100                                                              2BF       30/100                                                              3A        68.1                                                                3B        26.5                    50/30                                                 10 (s.c.)               86/100                                                3 (i.v.)                86/300                                      3C        53                                                                  3H        9.7 (i.v.)                                                          3-I       30/100                                                              3J        30/10 (i.v.)                                                        3K        45.7                                                                3L        44                                                                  3M        10/100                                                              3N        40/100                                                              3-O       76                                                                  3P        71                                                                  3Q        40/100                                                              3R        40/100                                                              3S        40/100                                                              3T        53                                                                  3U        30/100                                                              3V        253.8                                                               3W        49                                                                  3Y        69                                                                  3AA       22                                                                  3AB       25                                                                  3AC       21                                                                  3AD       100/100                                                             3AF       138.6                                                               3AG       42                                                                  3AH       30/100                                                              3AJ       35                                                                  4A        16          53          0,12/100                                    4B        24,25,21,15 38,28,19    27.6                                                  6 (i.v.)                                                            4C        37                                                                  4D        24                                                                  5A        31          0/300                                                             20/1 (i.v.)                                                                   29/3 (i.v.)                                                                   30/10 (i.v.)                                                        5B        25          61          0/10                                                                          12/30                                                                         12/100                                      5C        19          20/30                                                             60/100                                                                        60/300                                                              5D        84          20/200                                                            57/3 (i.v.)                                                                   29/1 (i.v.)                                                         5E        38/150                                                                        40/300                                                              5F        76                                                                  6         83          0/100                                                             0/10 (i.v.) 0/300                                                             0/30 (i.v.)                                                                   13/30 (s.c.)                                                        7         40          0/300                                                   8A        32                      62/30                                       8B        35/100                                                              9         27/300                                                                        20/30 (s.c.)                                                        10        0/30                                                                          7/30 (s.c.)                                                         11        20/30                                                                         13/30 (s.c.)                                                        12        13/30                                                                         0/30                                                                13A       139                                                                 13B       0/100                                                               13C       20/100                                                              14        40/100                                                              15        155                                                                 16A       10/100                                                              16B       20/100                                                              17        7/30        33/100 (s.c.)                                                     6.6 (s.c.)                                                          18        30/100                                                              19        40/100                                                              20A       128                                                                 20B       40/100                                                              21        31                                                                  22        66.8                                                                23A       85                                                                  23B       39                                                                  25A (r)   82.5                                                                25B       42                                                                  26A       40/100                                                              26B       40/100                                                              26C       30/100                                                              26D       30/100                                                              26E       73.1                                                                26F       61                                                                  26G       20/100                                                              27A       20.7                                                                27B       59.8                                                                27C       29.4                                                                27D       30                                                                  28        90/100                                                              29A       60,80/100                                                           29B       60,70/100                                                           29C       0/100                                                               30        10/100                                                              31A       58                                                                  31C       53                                                                  31F       0/3 (i.v.)                                                          31G       133                                                                 31H       56                                                                            30/100 (i.c.v.)                                                               80/10 (i.v.)                                                        31-I      31,40,88/100                                                        31J       10/100                                                              31K       28                                                                  31L       32                                                                  31M       26                                                                  31N       90,100/100                                                          31-O      100/100                                                             32        85                                                                  33        20/100                                                              ______________________________________                                         (r) N=B is amino                                                         

The 3-R₃ -carbonyl-1-aminoalkyl-1H-indoles of formulas I, Ia and Ib ofthe invention were also tested in the developing adjuvant arthriticassay, the plasma fibronectin assay and the pleurisy macrophage assay inrats. Data so-obtained, expressed as p-values as a measure of thestatistical significant of the results for each of the parametersmeasured, i.e. inhibition of inflammation of non-injected paw (NIP) andinjected paw (right pay volume or RPV), lowering of plasma fibronectinlevels (FN) and inhibition of macrophage accumulation in the pleuralcavity (MAC), are given in Table C. Compounds were considered active atp≦0.05 levels. Non-statistically significant results as "--".

                  TABLE C                                                         ______________________________________                                        Example     NIP    RPV        FN   MAC                                        ______________________________________                                        1B (s)      0.01   0.01       --                                              1F          0.01   0.01       --                                              1I          0.01   0.01       0.01 0.01                                       1U          --     --         --                                              1AC         --     --         --                                              1AO         --     --         --                                              1AP         --     --         --                                              1AW                                --                                         1BA         --     --         0.01                                            1BB         --     --         --                                              1BD         --     --         --                                              1BE         --     0.05       --                                              1BL         0.01   0.05       0.01                                            1BM         0.01   0.01       0.01 0.01                                       1BN                                --                                         1BO         --     0.01       0.05                                            1BP         0.01   0.01       --                                              1BQ (t)     0.01   0.01       0.01 0.01                                       1BR         0.01   0.01       0.01 --                                         1BZ         0.05   0.01       0.01 --                                         1CC         --     --         --                                              1CE         --     --         --                                              1CF         0.01   0.01       --                                              1CG         0.01   0.01       0.01 --                                         1CH         --     --         --                                              1CJ         0.01   0.01       --   --                                         1CL         --     --         0.01                                            1CM         --     0.01       --   --                                         1CO         0.01   0.01       --                                              1CP         0.01   0.01       0.01 0.01                                       2C          0.01   0.01       0.01 0.01                                       2E          0.01   0.01       --   --                                         2R          --     --         --                                              2S          --     --         --                                              2U          --     --         0.01                                            2V          --     --         --                                              2Y          0.05   --         --                                              2AA         --     --         --                                              2AB         --     --         --                                              2AC         0.05   --         --                                              2AD         --     --         --                                              2AE         0.01   0.01       --                                              2AF         0.01   0.01       --                                              2AG         0.01   --         0.01                                            2AI         0.01   0.01       0.01                                            2AK         --     --         --                                              2AN         --     --         --                                              2AO         0.01   0.01       0.01 0.05                                       2AQ                                --                                         2AS         --     --         --                                              2AT         --     --         --                                              2AU         --     --         0.05                                            2AV         --     --         --   --                                         2AW         --     --         --   0.05                                       2AX         --     --         --   --                                         2AY         0.01   0.05       --                                              2BB         --     0.01       0.05 --                                         2BF         --     0.01       0.01 --                                         3D          --     --         --                                              3E          0.01   --         --                                              3F          0.05   0.01       --                                              3G          --     --         --                                              3K          --     0.01       0.05                                            3T          --     0.01       --   --                                         3U          --     --         --                                              3W          0.01   0.01       0.05                                            3AF         --     0.01       --                                              3AG         0.01   0.01       0.01 --                                         3AH         0.01   --         0.01 --                                         3AI         0.01   0.01       0.05                                            3AJ         0.01   0.01       0.05 --                                         6           --     --         0.05 --                                         13B         --     --         0.01 --                                         13C         --     --         --   --                                         16A         0.05   --         --                                              19          --     --         --                                              20A         --     --         0.05 --                                         20B         --     --         --   --                                         21          --     --         --                                              22          0.01   0.01       --   0.05                                       23A         0.01   0.01       0.01 --                                         23B         0.01   0.01       0.01 --                                         24          0.05   0.01       --                                              25A                                --                                         25B         --     --         --                                              26E         --     --         --                                              26F         0.05   0.01       --                                              26G         --     --         0.01 --                                         27A         0.05   0.01       --                                              27B         0.05   0.01       --                                              27D         0.01   0.01       --                                              29A         0.05   0.01       --                                              29B                                --                                         31A         0.01              0.01 --                                         31B         0.01              --                                              31H         0.01              --                                              31J         0.05              --                                              31L         0.05   0.01       --   --                                         31M         0.01              --   0.01                                       31N         0.01   0.01       --   --                                         31-O        0.01   0.01       --   --                                         32          0.01   0.01       0.05                                            ______________________________________                                         (s) The maleate salt                                                          (t) The lower melting polymorph                                          

Certain species of the intermediate 2-R₂ -3-(R₃ -carbonyl)-indoles offormula II were also tested and found active in one or more of theacetylcholine-induced abdominal construction test (Ach), the developingadjuvant arthritic assay (NIP and RPV), the fibronectin assay FN) andthe pleurisy macrophage assay MAC). Data so-obtained, expressed asdescribed above, are given in Table D.

                  TABLE D                                                         ______________________________________                                        Prepn.  Ach       NIP    RPV     FN   MAC                                     ______________________________________                                        1F       0/100    --     --      --                                           1AJ                                   --                                      1AK     20/100    --     --      --   0.05                                    1AL     20/100    0.01   --      0.01 0.01                                    1AM               --     --      0.01                                         1AN               0.01   0.01    --   --                                      1AO     40/100                                                                1AQ               0.01   0.01    0.01                                         ______________________________________                                    

Certain species of the intermediate 2-R₂ -1-aminoalkyl-1H-indoles offormula III were tested and found active in the acetylcholine-inducedabdominal constriction test. Thus2-methyl-1-[1-methyl-2-(4-morpholinyl)ethyl]-1H-indole methanesulfonatehydrate (Preparation 5A) produced 40% inhibition at 300 mg./kg. (p.o.),and the ED₅₀ of5-fluoro-2-methyl-1-(1-methyl-2dimethylaminoethyl)-1H-indole(Preparation 8) was found to be 25 mg./kg/ (p.o.).

I claim:
 1. A compound having the formula: ##STR18## wherein: R₂ ishydrogen, lower-alkyl, chloro, phenyl or benzoyl (or phenyl or benzoylsubstituted by from one to two substituents selected from halo,lower-alkyl, lower-alkoxy, hydroxy, amino, lower-alkylmercapto,lower-alkylsulfinyl or lower-alkylsulfonyl);R₃ is cyclohexyl,lower-alkoxycyclohexyl, phenyl (or phyenyl substituted by from one totwo substituents selected from halo, lower-alkoxy, hydroxy, benzyloxy,lower-alkyl, nitro, amino, lower-alkylamino, di-lower-alkylamino,lower-alkoxy-lower-alkylamino, lower-alkanoylamino, benzoylamino,trifluroracetylamino, lower-alkyl-sulfonylamino, carbamylamo,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, cyano,formyl and oximinomethylene), methylenedioxyphenyl, 3- or4-hydroxy-1-piperidinylphenyl, 1-piperazinylphenyl,(1H-imidazol-1-yl)phenyl, (1-pyrrolyl)phenyl, aminomethylphenyl,guanidinylmethylphenyl, N-cyanoguanidinylmethylphenyl, styryl,lower-alkyl-substituted-styryl, fluorosubstituted-styryl, 2- or4-biphenyl, 1- or 2-naphthyl (or1- or 2-naphthyl substituted by from oneto two substituents selected from lower-alkyl, lower alkoxy, hydroxy,bromo, chloro, fluoro, lower-alkoxycarbonyl, carbamyl, cyano,lower-alkyl-mercapto, lower-alkylsulfinyl, lower-alkylsulfonyl andtrifluoromethyl), thienyl, furyl, benzofuryl, benzothienyl, quinolyl, or(N-lower-alkyl)pyrrolyl; R₄ is hydrogen or from one to two substituentsselected from lower-alkyl, hydroxy, lower-alkoxy and halo in the 4-, 5-,6- or 7-positions; C=Z is C=O or C=NOH; and N=B is azido, amino,N-lower-alkylamino, N,N-dilower-alkylamino,N-(hydroxy-lower-alkyl)amino, N,N-di-(hydroxy-lower-alkyl)amino,N-lower-alkyl-N-(hydroxy-lower-alkyl)amino,N-(lower-alkoxy-lower-alkyl)amino, N-(halo-n-propyl)amino,4-morpholinyl, 2-lower-alkyl-4-morpholinyl,2,6-di-lower-alkyl-4-morpholinyl, 4-thiomorpholinyl,4-thiomorpholinyl-S-oxide, 4-thiomorpholinyl-S,S-dioxide, 1-piperidinyl,3-or 4-hydroxy-1-piperidinyl, 3- or 4-lower-alkanoyloxy-1-piperidinyl,3- or 4-amino-1-piperidinyl, 3- or4-(N-lower-alkanoylamino)-1-piperidinyl,2-cyclohexylmethyl-1-piperidinyl, 1pyrrolidinyl,3-hydroxy-1-pyrrolidinyl, 1-azetidinyl, 1-piperazinyl,4-lower-alkyl-1piperazinyl, 4-lower-alkanoyl-1-piperazinyl,4-carbo-lower-alkoxy-1-piperazinyl, hexahydro-4H-1,4-diazepin-4-yl orthe N=BN-oxides thereof; or an acid addition salt thereof.
 2. A compoundaccording to claim 1 wherein:R₂ is lower-alkyl; R₃ islower-alkoxy-substituted phenyl or 1-naphthyl; R₄ is hydrogen orhalogen; C=Z is C=O; and N=B is azido, amino, N-lower-alkylamino,N,N-dilower-alkylamino, 4-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl or1 -azetidinyl; or an acid-addition salt thereof.
 3. A compound accordingto claim 2 wherein R₄ is fluoro. 4.1-[2-Hydroxy-3-(4-morpholinyl)propyl]-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1H-indoleor an acid-addition salt thereof according to claim 3,
 5. An analgesic,anti-rheumatic or anti-inflammatory composition for the relief of painor rheumatic or inflammatory conditions which comprises apharmaceutically acceptable carrier and, as the active componentthereof, an effective analgesic, anti-rheumatic or anti-inflammatoryamount of a compound according to claim
 1. 6. A method for the relief ofpain or rheumatic or inflammatory conditions in a patient requiring suchtreatment which comprises administering orally or parenterally to suchpatient a medication in solid or liquid dosage form containing, as theactive component thereof, an effective analgesic, anti-rheumatic oranti-inflammatory amount of a compound according to claim 1.